Adding HPO terms to X-linked sideroblastic anemia and spinocerebellar ataxia (XLSA-A)

[D0ctorNo]

NEW VERSION:

In case the old post was a bit confusing, I have created a new and hopefully better version and corrected many errors in the process. I hope all is well now and apologise for any inconvenience this may have caused and hope that this improvement will make it into the next update. As always, if there are any uncertainties or problems please do not hesitate to contact me.

Below are the text passages/quotes with the symptoms of the affected patients. I have only taken the text passages/quotes that describe the presence of a symptom and not those that exclude one. Hematologic abnormalities listed in a table of a publication are listed separately under the patient's text passage.

Under each patient case is a precise list of the respective phenotypes present. A summary of ALL phenotypes with their frequency (respective) that exist for this disease are listed as intended under section 'HPO ID and Name', including those that are already annotated/linked to OMIM and orphanet.

The most recent publication from 2021 by Xiong S, et al. (last publication at the bottom) provides a very good and detailed overview of all other publications mentioned here and their clinical findings. Nevertheless, not all the figures in the publication are correct, and in some places their calculation of affected individuals with certain phenotypes was somewhat generous.

Disease ID and Name OMIM:301310 Anemia, sideroblastic, and spinocerebellar ataxia ORPHA:2802 X-linked sideroblastic anemia and spinocerebellar ataxia

HPO ID and Name New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that were imported from orphanet and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while already exisiting OMIM annotations are just blank. Two HPO-Terms from Orphanet (Global development delay and Abnormality of movement) were not mentioned literally in any of these publications, but the symptoms described in these publications indicate their presence even though these two HPO-Terms might be very general. It is therefore up to you to decide wether to include these two terms. The total number of people affected by this disease is 18, but only the people affected in each case were taken into account for the frequency.

PHENOTYPES AND THEIR FREQUENCY: (respective)

(-)++HP:0001263 Global developmental delay (15/17) PMID:4045952 , PMID:11050011 , PMID:11118249 , PMID:26242992 , PMID:34354969 HP:0002470 Nonprogressive cerebellar ataxia (11/12) OMIM annotation (-)++HP:0001251 Ataxia (15/17) PMID:4045952 , PMID:11050011 , PMID:11118249 , PMID:26242992 , PMID:34354969 HP:0001310 Dysmetria (3/4) OMIM annotation HP:0002080 Intention tremor (1/4) OMIM annotation (-)++HP:0001903 Anemia (9/11) PMID:4045952 , PMID:11050011 , PMID:11118249 , PMID:34354969 HP:0004840 Hypochromic microcytic anemia (4/6) OMIM annotation HP:0001924 Sideroblastic anemia (3/6) OMIM annotation ++HP:0011273 Anisocytosis (3/9) PMID:4045952 , PMID:11118249 , PMID:22398176 ++HP:0004447 Poikilocytosis (4/9) PMID:4045952 , PMID:11118249 , PMID:22398176 ++HP:0031020 Bone marrow hypercellularity (2/4) PMID:4045952 HP:0001347 Hyperreflexia (5/8) OMIM annotation HP:0002169 Clonus (2/4) OMIM annotation HP:0003487 Babinski sign (3/4) OMIM annotation ++HP:0012187 Increased erythrocyte protoporphyrin concentration (8/11) PMID:4045952 , PMID:11050011 , PMID:11118249 , PMID:22398176 (-)++HP:0001511 Intrauterine growth retardation (3/7) PMID:4045952 , PMID:11050011 , PMID:34354969 (-)++HP:0000486 Strabismus (3/5) PMID:4045952 , PMID:22398176 ++HP:0012132 Erythroid hyperplasia (1/4) PMID:4045952 HP:0001260 Dysarthria (15/18) OMIM annotation ++HP:0002463 Language impairment (3/7) PMID:4045952 , PMID:11050011 , PMID:34354969 (-)++HP:0002167 Abnormality of speech or vocalization (15/18) PMID:4045952 , PMID:11050011 , PMID:11118249 , PMID:22398176 , PMID:26242992 , PMID:34354969 (from all six PubMed publications) HP:0002075 Dysdiadochokinesis (4/10) OMIM annotation ++HP:0002403 Positive Romberg sign (1/4) PMID:4045952 ++HP:0001288 Gait disturbance (7/10) PMID:4045952 , PMID:11118249 , PMID:22398176 , PMID:34354969 (-)++HP:0100022 Abnormality of movement (15/16) PMID:4045952 , PMID:11118249 , PMID:22398176 , PMID:26242992 , PMID:34354969 ++HP:0100543 Cognitive impairment (1/2) PMID:11050011 ++HP:0000980 Pallor (1/2) PMID:11050011 ++HP:0001824 Weight loss (2/3) PMID:11050011 , PMID:34354969 ++HP:0001321 Cerebellar hypoplasia (7/8) PMID:11050011 , PMID:26242992 ++HP:0004322 Short stature (3/3) PMID:11050011 , PMID:34354969 (-)++HP:0000639 Nystagmus (9/13) PMID:11050011 , PMID:11118249 , PMID:26242992 , PMID:34354969 ++HP:0001315 Reduced tendon reflexes (3/3) PMID:11050011 , PMID:34354969 ++HP:0002172 Postural instability (9/12) PMID:11118249 , PMID:22398176 , PMID:26242992 , PMID:34354969 ++HP:0100753 Schizophrenia (1/4) PMID:11118249 ++HP:0006897 Abducens palsy (1/4) PMID:11118249 ++HP:0020081 Pappenheimer bodies (3/5) PMID:11118249 , PMID:22398176 ++HP:0001272 Cerebellar atrophy (2/4) PMID:11118249 ++HP:0002363 Abnormal brainstem morphology (2/4) PMID:11118249 ++HP:0034280 Target cells (1/4) PMID:11118249 ++HP:0032550 Howell-Jolly bodies (1/4) PMID:11118249 ++HP:0000726 Dementia (1/4) PMID:11118249 ++HP:0000602 Ophthalmoplegia (5/6) PMID:26242992 (-)++HP:0001252 Hypotonia (3/7) PMID:26242992 , PMID:34354969 ++HP:0001618 Dysphonia (2/6) PMID:26242992 ++HP:0001336 Myoclonus (1/6) PMID:26242992 ++HP:0000716 Depression (1/6) PMID:26242992 ++HP:0001250 Seizure (1/1) PMID:34354969 ++HP:0000717 Autism (1/1) PMID:34354969 ++HP:0001992 Organic aciduria (1/1) PMID:34354969 ++HP:0000028 Cryptorchidism (1/1) PMID:34354969 ++HP:0025373 Interictal EEG abnormality (1/1) PMID:34354969 ++HP:0006999 Basal ganglia gliosis (1/1) PMID:34354969 ++HP:0012751 Abnormal basal ganglia MRI signal intensity (1/1) PMID:34354969

Further information (Frequency, Onset, Pubmed-references, Comments)

PMID: 4045952 Quotes: We report two families in which a non-progressive spinocerebellar syndrome and a sideroblastic anaemia are segregating together in an X linked recessive fashion.

Summary of findings The five affected males reported here have a neurological disorder characterised by non-progressive ataxia and incoordination which was apparent by one year of age.

[Patient IV.5] At one year of age he had developmental delays because of truncal ataxia, dysmetria, and tremulousness.

At 2 1/2 years of age, when admitted to hospital for an unrelated illness, he was found to be anaemic (table 1).

Peripheral blood smear showed microcytic, hypochromic red cells with anisocytosis and cigar-shaped cells

Bonemarrow examination showed a myeloid to erythroid ratio of 3:1,...

He had pathologically brisk deep tendon reflexes in the lower extremities, unsustained ankle clonus, truncal ataxia when sitting, and a shuffling, ataxic gait. Muscle tone was normal. Plantar reflexes were extensor.

Hematocrit: Normal MCV: Decreased (68fl) | Normal range: Usually around 78-98fl Blood smear: dimorphic red cell populiton (not desirable) free erythrocyte protoporphyrin (FEP): Raised (16.8 μg/g haem) | Normal range:1-5μg/g haem Ring sideroblasts: Present

Phenotypes present in this patient (according to my understanding): HP:0001263 Global developmental delay HP:0002470 Nonprogressive cerebellar ataxia HP:0001251 Ataxia HP:0001310 Dysmetria HP:0002080 Intention tremor HP:0001903 Anemia HP:0004840 Hypochromic microcytic anemia HP:0001924 Sideroblastic anemia HP:0011273 Anisocytosis HP:0004447 Poikilocytosis (cigar-shaped cells and a dimorphic red cell populution in a blood smear can probably regarded as such) HP:0031020 Bone marrow hypercellularity (Myeloid hyperplasia / myeloid to erythroid ratio of 3:1) HP:0001347 Hyperreflexia HP:0002169 Clonus HP:0001288 Gait disturbance HP:0100022 Abnormality of movement HP:0003487 Babinski sign (Extensor plantar reflexes) HP:0012187 Increased erythrocyte protoporphyrin concentration

[Patient III.1] who was 33 years old, had weighed 2.3 kg at birth. Because of a non-progressive neurological disorder, he had not walked independently until 9 years of age. He had had strabismus surgery in childhood.

Anaemia was discovered during a routine physical examination at 17 years of age (table 1).

His peripheral smear showed microcytic, hypochromic red cells with marked poikilocytosis, shift to the left, and heavy stippling. Bone marrow examination showed hypercellularity with an E:G ratio of 3:1 and increased iron stores with 80% ring sideroblasts.

He had mild dysarthria, mild bilateral finger-to-nose dysmetria, difficulty with rapid alternating movements, mild heel-to-shin ataxia, an abnormal Romberg test, poor tandem walking, and a moderately ataxic gait with toe walking. He had no nystagmus. His deep tendon reflexes were active but normal, except at the knees where they were pathologically brisk. There was no patellar or ankle clonus.

Hematocrit: Normal MCV: Decreased (67fl) | Normal range: Usually around 78-98fl Blood smear: dimorphic red cell populiton (not desirable) free erythrocyte protoporphyrin (FEP): Raised (184 mol/mol haem) Normal range:9-89mol/mol haem Ring sideroblasts: Present

Phenotypes present in this patient: HP:0001511 Intrauterine growth retardation HP:0001263 Global developmental delay HP:0002470 Nonprogressive cerebellar ataxia HP:0001251 Ataxia HP:0000486 Strabismus HP:0001903 Anemia HP:0004840 Hypochromic microcytic anemia HP:0001924 Sideroblastic anemia HP:0004447 Poikilocytosis HP:0031020 Bone marrow hypercellularity HP:0012132 Erythroid hyperplasia (E:G ratio of 3:1) HP:0001260 Dysarthria HP:0002167 Abnormality of speech or vocalization HP:0001310 Dysmetria HP:0002075 Dysdiadochokinesis HP:0002403 Positive Romberg sign (an abnormal Romberg test probably indicates that) HP:0001288 Gait disturbance HP:0100022 Abnormality of movement (poor tandem walking or known as Impaired tandem gait) HP:0001347 Hyperreflexia HP:0012187 Increased erythrocyte protoporphyrin concentration

[Patient IV.12] Truncal instability prevented independent standing, although he was able to walk with support from the age of one year. Language was normal at 2 1/2 years but mild articulation difficulties were present.

He had had surgery for accommodative esotropia.

Anaemia was initially diagnosed at 6 months of age (table 1).

Tendon reflexes were normal in the upper extremities and pathologically brisk in the lower extremities with unsustained ankle clonus and bilateral extensor plantar responses. There was mild truncal ataxia and he was unable to walk without assistance.

Hematocrit: Normal MCV: Decreased (58fl) | Normal range: Usually around 78-98fl Blood smear: dimorphic red cell populiton (not desirable) free erythrocyte protoporphyrin (FEP): Raised (140 mol/mol haem) | Normal range:9-89mol/mol haem Ring sideroblasts: unknown

Phenotypes present in this patient: HP:0001263 Global developmental delay HP:0002167 Abnormality of speech or vocalization HP:0001260 Dysarthria HP:0000486 Strabismus (accommodative esotropia) HP:0001903 Anemia HP:0001347 Hyperreflexia HP:0002169 Clonus HP:0003487 Babinski sign HP:0002470 Nonprogressive cerebellar ataxia HP:0001251 Ataxia HP:0100022 Abnormality of movement HP:0012187 Increased erythrocyte protoporphyrin concentration

[Patient IV.13] Patient IV. 13 was a 23 month old male born at term, weighing 2.9 kg.

His early developmental milestones were normal, but he made no progress in gross motor development after 12 months of age. He was unable to stand independently and walked only with support.

At 21 months of age he had normal receptive language but delayed expressive language and articulation difficulty.

Anaemia was diagnosed during the first 6 months of life (table 1).

He had marked ataxia while sitting which usually required him to assume a tripod position, marked dysmetria, pathologically brisk deep tendon reflexes in his lower extremities, and a left extensor plantar response.

Hematocrit: Normal MCV: Decreased (58fl) | Normal range: Usually around 78-98fl free erythrocyte protoporphyrin (FEP): unknown Ring sideroblasts: unknown

Phenotypes present in this patient: HP:0002470 Nonprogressive cerebellar ataxia HP:0001251 Ataxia HP:0001263 Global developmental delay HP:0002463 Language impairment HP:0001260 Dysarthria HP:0002167 Abnormality of speech or vocalization HP:0001903 Anemia HP:0001310 Dysmetria HP:0001347 Hyperreflexia HP:0003487 Babinski sign

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): (-)++HP:0001263 Global developmental delay (4/4) HP:0002470 Nonprogressive cerebellar ataxia (4/4) (-)++HP:0001251 Ataxia (4/4) HP:0001310 Dysmetria (3/4) HP:0002080 Intention tremor (1/4) (-)++HP:0001903 Anemia (4/4) HP:0004840 Hypochromic microcytic anemia (2/4) HP:0001924 Sideroblastic anemia (2/4) ++HP:0011273 Anisocytosis (1/4) ++HP:0004447 Poikilocytosis (2/4) ++HP:0031020 Bone marrow hypercellularity (2/4) HP:0001347 Hyperreflexia (4/4) HP:0002169 Clonus (2/4) HP:0003487 Babinski sign (3/4) ++HP:0012187 Increased erythrocyte protoporphyrin concentration (3/4) (-)++HP:0001511 Intrauterine growth retardation (1/4) (-)++HP:0000486 Strabismus (2/4) ++HP:0012132 Erythroid hyperplasia (1/4) HP:0001260 Dysarthria (3/4) ++HP:0002463 Language impairment (1/4) (-)++HP:0002167 Abnormality of speech or vocalization (3/4) HP:0002075 Dysdiadochokinesis (1/4) ++HP:0002403 Positive Romberg sign (1/4) ++HP:0001288 Gait disturbance (2/4) (-)++HP:0100022 Abnormality of movement (3/4)

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PMID: 11050011 [II-1] The proband in family 1 (II-1; Figure1D) was a white male (DOB, 12/22/66) born at a low birthweight (2495 g) to nonconsanguineous parents. From early infancy, the proband had mild postnatal growth retardation and substantially impaired gross motor and cognitive development. He did not sit unsupported until age 4, when congenital ataxia was diagnosed. By age 6, he managed to walk with support and subsequently could walk short distances unsupported. He has used simple language from age 5, and he attended a special school where he exhibited severe, static intellectual impairment.

In 4 decades there has been no evidence of progression of ataxia or intellectual impairment, and the proband has been in good physical and mental health. At age 13, his hemoglobin level measured 10.1 g/dL, and his erythrocytes were microcytic. Computed tomography of the brain at age 18 showed striking, selective cerebellar hypoplasia, but no further action was taken until the proband was brought for examination at age 22 year with pallor and weight loss; sideroblastic anemia and nonprogressive cerebellar ataxia were diagnosed.

His younger brother [II-1] was slightly more anemic (Hb, 9.9 g/dL; MCH, 19.6 pg; MCV, 60.2 fL).

Total erythrocyte protoporphyrin: Raised (25.7 μmol/L) Normal range: 0.4-1.7μmol/L

Phenotypes present in this patient: HP:0001511 Intrauterine growth retardation HP:0001263 Global developmental delay HP:0002470 Nonprogressive cerebellar ataxia HP:0001251 Ataxia HP:0002463 Language impairment HP:0100543 Cognitive impairment HP:0001903 Anemia HP:0004840 Hypochromic microcytic anemia HP:0000980 Pallor HP:0001824 Weight loss HP:0001924 Sideroblastic anemia HP:0001321 Cerebellar hypoplasia HP:0012187 Increased erythrocyte protoporphyrin concentration

[II-2] A younger brother (II-2, DOB 7/26/69), who had a similar phenotype, underwent diagnosis at this time and also was found to be affected but has not received pyridoxine supplementation. At age 25, the proband's blood studies (Table2) revealed anemia (Hb, 10.8 g/dL) with hypochromic (MCH, 20.0 pg) microcytic (MCV, 62.2 fL) erythrocytes,..

Total erythrocyte protoporphyrin: Raised (19.5 μmol/L) Normal range: 0.4-1.7μmol/L

Comment: It is your decision whether you count his brother's [II-1] phenotypes as his as well Phenotypes present in this patient: HP:0001903 Anemia HP:0004840 Hypochromic microcytic anemia HP:0012187 Increased erythrocyte protoporphyrin concentration

[II-1] and [II-2] On recent examination, both affected brothers are nondysmorphic and have reduced heights (157.5 and 160 cm, respectively).

The brothers have cerebellar signs including nystagmus, dysarthria, past pointing, and dysdiadochokinesis.

Tendon reflexes could not be elicited at the elbows or ankles and were diminished at the knees.

When the proband's blood was recently evaluated (Western Infirmary, Glasgow, UK) at age 33, he continued to display hypochromic, microcytic anemia, and his affected younger brother continued to exhibit slightly more anemia (Table 2).

Phenotypes that are mentioned in both patients: HP:0004322 Short stature HP:0000639 Nystagmus HP:0001260 Dysarthria HP:0002167 Abnormality of speech or vocalization HP:0002075 Dysdiadochokinesis HP:0001315 Reduced tendon reflexes

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): (-)++HP:0001511 Intrauterine growth retardation (1/2) (-)++HP:0001263 Global developmental delay (1/2) HP:0002470 Nonprogressive cerebellar ataxia (1/2) (-)++HP:0001251 Ataxia (1/2) ++HP:0002463 Language impairment (1/2) ++HP:0100543 Cognitive impairment (1/2) (-)++HP:0001903 Anemia (2/2) HP:0004840 Hypochromic microcytic anemia (2/2) ++HP:0000980 Pallor (1/2) ++HP:0001824 Weight loss (1/2) HP:0001924 Sideroblastic anemia (1/2) ++HP:0001321 Cerebellar hypoplasia (1/2) ++HP:0012187 Increased erythrocyte protoporphyrin concentration (2/2) ++HP:0004322 Short stature (2/2) (-)++HP:0000639 Nystagmus (2/2) (-)++HP:0002167 Abnormality of speech or vocalization (2/2) HP:0001260 Dysarthria (2/2) HP:0002075 Dysdiadochokinesis (2/2) ++HP:0001315 Reduced tendon reflexes (2/2)

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PMID: 11118249 Our affected patients all show evidence of progression from the fifth decade. [PATIENT III.2] He did not walk until he was 11 years old and improved so that he could walk independently by the age of 17. His walking deteriorated since the age of 40, and he has been wheelchair bound for 12 years. Schizophrenia was diagnosed in his 20s and he has remained on phenothiazine medication since.

Examination showed a spastic and ataxic gait. He had a left abducens palsy, unchanged since childhood according to his mother. He had nystagmus on upbeat and lateral gaze. He had some mild restriction of upgaze. He was markedly dysarthric. Comparison with an examination 5 years previously showed some evidence of progression. He now has marked fingernose ataxia and increased tone on his right side with a mild right upper motor neuron VIIth nerve palsy. He had a stiff legged ataxic gait.

Of note he had a mild anaemia and raised FEP concentrations. Also Pappenheimer bodies were visible on his blood film (fig 3), especially prominent in view of his splenectomy. Brain MRI showed a markedly atrophic cerebellum, with some atrophy of the pons and medulla (fig 4).

MCV: Normal (84fl) free erythrocyte protoporphyrin: Raised (3.1 μmol/litre) | Normal range: 0.4-1.7μmol/litre Ring sideroblasts: unknown Hemoglobin: Decreased (12.1 g/dl) | Normal range: 13-17 g/dl

Blood film: Anisocytosis, Poikilocytosis, Target cells, Howell-Jolly bodies, Pappenheimer bodies

Phenotypes present in this patient: HP:0001263 Global developmental delay HP:0100022 Abnormality of movement HP:0100753 Schizophrenia HP:0001288 Gait disturbance HP:0006897 Abducens palsy HP:0000639 Nystagmus HP:0001260 Dysarthria HP:0002167 Abnormality of speech or vocalization HP:0001251 Ataxia HP:0001903 Anemia HP:0012187 Increased erythrocyte protoporphyrin concentration HP:0020081 Pappenheimer bodies HP:0001272 Cerebellar atrophy HP:0002363 Abnormal brainstem morphology (atrophy of the pons and medulla) HP:0011273 Anisocytosis HP:0004447 Poikilocytosis HP:0034280 Target cells HP:0032550 Howell-Jolly bodies

[PATIENT III.3] He did not start walking until he was 3 years old, and was always below average in his motor abilities, although he was able to ride a bicycle.

His walking deteriorated since the age of 45. He had double vision as a teenager; an operation failed to restore binocular vision.

Examination demonstrated broken pursuit eye movements and some hypometric saccades. He had some perioral fasciculation. He had a concomitant divergent squint but no restriction of eye movements.

He had finger-nose ataxia, more marked on the left side.

He had a wide based gait and required no walking aids.

Key abnormalities include a low mean corpuscular volume, a raised FEP concentration, Pappenheimer bodies on the blood film, and ring sideroblasts in the bone marrow. Brain MRI showed selective atrophy of the cerebellum, with the pons and medulla of normal size (fig 4).

MCV: Decreased (77fl) | Normal range:78-98fl Hemoglobin: Normal (14.3 g/dl) | Normal range: 13-17g/dl Free erythrocyte protoporphyrin: Raised (4.9 μmol /litre) | Normal range: 0.4-1.7 μmol /litre Ring Sideroblasts: Present

Blood film: Hypochromic red cells, Pappenheimer bodies

Phenotypes present in this patient: HP:0001263 Global developmental delay HP:0100022 Abnormality of movement HP:0001251 Ataxia HP:0001288 Gait disturbance HP:0012187 Increased erythrocyte protoporphyrin concentration HP:0020081 Pappenheimer bodies HP:0001272 Cerebellar atrophy HP:0002363 Abnormal brainstem morphology

[PATIENT II.1] This man, aged 78, lived in a nursing home, and was unavailable for examination. He was reported by his sister to have always had trouble walking, using a wheelchair to go out as a child but being able to walk until the age of 74. He is thought to have a moderate dementia.

MCV: Normal (83fl) | Normal range: 78-98fl Hemoglobin: Decreased (10.2 g/dl) | Normal range: 13-17g/dl free erythrocyte protoporphyrin: unkown

Phenotypes present in this patient: HP:0100022 Abnormality of movement HP:0000726 Dementia HP:0001903 Anemia

[PATIENT II.2] This man, aged 63, was the product of a normal pregnancy but did not walk until the age of 5 years.

His gait was always ataxic and he was unable to ride a bicycle. He always had slurred speech. Since the age of 58 his balance started to deteriorate slowly and he had occasional falls. Examination showed that he was obviously dysarthric. He had hypometric saccades and nystagmus.

Reflexes were brisk but plantars were flexor. He had bilateral finger, nose, and heel shin ataxia and bilateral dysdiadochokinesia. He had a wide based ataxic gait...

MCV: Decreased (74fl) | Normal range: 78-98fl Hemoglobin: Normal (13.5g/dl) | Normal range: 13-17 Free erythrocyte protoporphyrin: unknown Ring sideroblasts: unkown

Phenotypes present in this patient: HP:0001263 Global developmental delay HP:0001251 Ataxia HP:0002172 Postural instability HP:0001288 Gait disturbance HP:0100022 Abnormality of movement HP:0002167 Abnormality of speech or vocalization HP:0001260 Dysarthria HP:0000639 Nystagmus HP:0001347 Hyperreflexia HP:0002075 Dysdiadochokinesis

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): (-)++HP:0001263 Global developmental delay (3/4) (-)++HP:0100022 Abnormality of movement (4/4) ++HP:0001288 Gait disturbance (3/4) ++HP:0002172 Postural instability (1/4) ++HP:0100753 Schizophrenia (1/4) ++HP:0006897 Abducens palsy (1/4) (-)++HP:0000639 Nystagmus (2/4) HP:0001260 Dysarthria (2/4) (-)++HP:0001251 Ataxia (3/4) (-)++HP:0001903 Anemia (2/4) ++HP:0012187 Increased erythrocyte protoporphyrin concentration (2/4) ++HP:0020081 Pappenheimer bodies (2/4) ++HP:0001272 Cerebellar atrophy (2/4) ++HP:0002363 Abnormal brainstem morphology (2/4) ++HP:0011273 Anisocytosis (1/4) ++HP:0004447 Poikilocytosis (1/4) ++HP:0034280 Target cells (1/4) ++HP:0032550 Howell-Jolly bodies (1/4) ++HP:0000726 Dementia (1/4) (-)++HP:0002167 Abnormality of speech or vocalization (2/4) HP:0001347 Hyperreflexia (1/4) HP:0002075 Dysdiadochokinesis (1/4)

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PMID: 22398176 [just one patient in this case] When first seen around the age of 2 years, the child had no relevant medical antecedents, except for strabismus.

However, at the age of 2 years he was still unable to stand unsupported. Evaluation at the age of 27 months revealed disturbances of coordination in upper and lower limbs. His language development was normal but he had difficulties with articulation.

Seven months later, at the age of 2 years 10 months, he could hardly stand without support for 30 s. At the age of 3 years he could take a few steps with the greatest caution. At the age of 4 years 6 months he could stand without support during a few minutes but he still rapidly lost his balance when taking a few steps.

Peripheral blood smear showed microcytic, hypochromic red cells with anisocytosis, abnormally shaped cells and some Pappenheimer bodies. Bone marrow examination at the age of 2 years 5 months showed 5-10% ringed sideroblasts (Fig. 3)

In blood, total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) were measured according to the methods described by Piomelli 20 and by Hart and Piomelli 21; these measurements revealed a very high level of TEP 4656 μg/l RBC (normal range 200-550) and of ZnEP 4249 μg/l RBC (normal range 125-400 μg/l RBC).

MCV: Decreased (63.6fl) | Normal range: 78-100fl MCH: Decreased (20.7pg) | Normal range: 28-34pg Hemoglobin: Normal (11.6mg/dl) | Normal range: 10-13mg/l Total erythrocyte protoporphyrin: Raised (4656 μg/l) | Normal range: 200-500μg/l Zinc erythrocyte protoporphyrin (μg/l RBC): Raised (4249 μg/l) | Normal range: 125-400μg/l

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): (-)++HP:0000486 Strabismus (1/1) (-)++HP:0100022 Abnormality of movement (1/1) (-)++HP:0002167 Abnormality of speech or vocalization (1/1) HP:0001260 Dysarthria (1/1) ++HP:0002172 Postural instability (1/1) ++HP:0001288 Gait disturbance (1/1) ++HP:0011273 Anisocytosis (1/1) ++HP:0004447 Poikilocytosis (1/1) ++HP:0020081 Pappenheimer bodies (1/1) ++HP:0012187 Increased erythrocyte protoporphyrin concentration (1/1)

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PMID: 26242992 Magnetic resonance imaging (MRI) scans revealed hypoplasia of cerebellar hemispheres and vermis in affected males from the Buryat pedigree. Common neurological symptoms for all affected family members were development delay, difficulties in speech and coordination, limb and truncal ataxia and dysarthria (Supplementary Table 1). The patients examined were not able to sit without support any time before 15 months of age, or to walk independently before 7 years of age and to speak their first words before 4 years of age. For the majority of patients, nystagmus, ophthalmoplegia and increased tendon reflexes were observed.

Here, we report a novel mutation in ABCB7 that is a causative factor of cerebellar hypoplasia/atrophy and nonprogressive ataxia, thus further expanding the list of mutations in this gene linked to cerebellar ataxia.

However, the remarkable feature of our case is that the patients have nonprogressive ataxia without the classic symptoms of sideroblastic anemia.

Clinical findings in Supplementary Material File in publication: Suplementary table 1: Clinical findings in [Patient III-6]: Sitting without support(age): >10 months [Normal:9 months], Walking without support(age): 4 years [Normal:12-18months], Ataxia, Dysarthria, Ophthalmoplegia

Clinical findings in [Patient III-17]: Walking without support(age): 7 years [Normal:12-18months], First words spoken(age): 3 years [Normal:12months], Ataxia, Dysarthria, Nystagmus, Ophthalmoplegia

Clinical findings in [Patient III-18]: Walking without support(age): 7 years [Normal:12-18months], First words spoken(age): 4 years [Normal:12months], Ataxia, Dysarthria, Nystagmus, Ophthalmoplegia, Dysphonia

Clinical findings in [Patient III-30]: Sitting without support(age): 15 months [Normal:9months], Walking without support(age): 4 years [Normal:12-18months], First words spoken(age): 4 years [Normal:12months], Ataxia, Dysarthria, Ophthalmoplegia, Hypotonia, Dysphonia, Myoclonus, Depression

Clinical findings in [Patient IV-26]: Sitting without support(age): 14 months [Normal:9months], Walking without support(age): 4 years [Normal:12-18months], First words spoken(age): 4 years [Normal:12months], Ataxia, Dysarthria, Nystagmus, Ophthalmoplegia

Clinical findings in [Patient IV-40]: Sitting without support(age): 6 months [Normal:9months], Walking without support(age): 11 months [Normal:12-18months], First words spoken(age): 15 months [Normal:12months], Ataxia, Dysarthria, Nystagmus, Hypotonia

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): ++HP:0001321 Cerebellar hypoplasia (6/6) (-)++HP:0001263 Global developmental delay (6/6) (-)++HP:0002167 Abnormality of speech or vocalization (6/6) (-)++HP:0100022 Abnormality of movement (6/6) HP:0001260 Dysarthria (6/6) ++HP:0002172 Postural instability (6/6) (-)++HP:0001251 Ataxia (6/6) HP:0002470 Nonprogressive cerebellar ataxia (6/6) (-)++HP:0000639 Nystagmus (4/6) ++HP:0000602 Ophthalmoplegia (5/6) (-)++HP:0001252 Hypotonia (2/6) ++HP:0001618 Dysphonia (2/6) ++HP:0001336 Myoclonus (1/6) ++HP:0000716 Depression (1/6)

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PMID: 34354969 [just one patient in this case]

The proband was a 5-year-old boy who was admitted to our hospital for recurrent seizure and growth retardation for 4 years. He was born at 35 weeks with a birth weight of 2,000 g. He had nystagmus at the first month of age. Growth and motor delays were noted at early childhood. He can sit at 1 year of age. He was unable to walk unsupported while still rapidly losing his balance after taking a few steps at around 2 years of age. At the age of four, he can walk and speak a few words.

The patient had a history of anemia.

The patient's first generalized seizure occurred at 11 months of age.

Gesell Development Scales (GDS) estimated at 5 years old indicated severe to extremely severe delay (scores of Gesell gross motor, fine motor, visual motor, language, and social were 28, 37, 31, 24, and 30, respectively). Scores of the Checklist for Autism in Toddlers-23 (CHAT-23) and the Clancy Autism Behavior Scale (CABS) were 20 and 15, respectively, both of which indicated he might have autism.

At the age of 5 years and 4 months, his height (97.5 cm), weight (15 kg), and head circumference (44 cm) were under the third percentile. The bilateral testicles were not palpable in the scrotum. Neurological examination showed decreased tendon reflexes, and plantar responses were flexor. Decreased muscle tone in the proximal upper and lower limbs and normal muscle strength were found.

He had mild ataxic gait with wide-based steps. Nystagmus was noted. During his hospitalization, his hematological examinations showed mild normochromic anemia (Table 1). The examination of urinary organic acids showed significantly increased 2-hydroxyisobutyric acid, glycolic acid, oxalic acid, phosphoric acid, and glyceric acid (Table 1). Interictal electroencephalogram was found with spikes and sharp waves over the bilateral frontal region, anterior midline region, and centrotemporal region during both the waking and sleeping periods (Figure 1). MRI showed lacunar infarction in the left basal ganglia with glial proliferation around and small tiny left transverse sinus, sigmoid sinus, and internal jugular vein (Figure 2). Bilateral cryptorchidism was detected by ultrasonography (Figure 3). Because of the subtle anemia (Hb 113 g/l) without any symptoms, the patient's parents refused to perform the further examination.

Other clinical findings listet in the publication's 'Table 3' (not mentioned above):Ataxia gait, Dysarthria

Phenotype summary and their frequency in this publication (New phenotypes that are not yet associated with the disease and therefore still need to be added are labelled with a ++ before. Phenotypes that are already linked to orpha.net and can thus still be addad within OMIM annotations are labelled with a (-)++ before, while OMIM annotations are just blank.): ++HP:0001250 Seizure (1/1) (-)++HP:0001511 Intrauterine growth retardation (1/1) (-)++HP:0000639 Nystagmus (1/1) (-)++HP:0001263 Global developmental delay (1/1) ++HP:0002463 Language impairment (1/1) ++HP:0002172 Postural instability (1/1) (-)++HP:0001251 Ataxia (1/1) (-)++HP:0100022 Abnormality of movement (1/1) (-)++HP:0001903 Anemia (1/1) ++HP:0000717 Autism (1/1) ++HP:0004322 Short stature (1/1) ++HP:0001824 Weight loss (1/1) ++HP:0001315 Reduced tendon reflexes (1/1) (-)++HP:0001252 Hypotonia (1/1) ++HP:0001288 Gait disturbance (1/1) ++HP:0001992 Organic aciduria (1/1) ++HP:0025373 Interictal EEG abnormality (1/1) ++HP:0006999 Basal ganglia gliosis (1/1) ++HP:0012751 Abnormal basal ganglia MRI signal intensity (1/1) ++HP:0000028 Cryptorchidism (1/1) HP:0001260 Dysarthria (1/1) (-)++HP:0002167 Abnormality of speech or vocalization (1/1)

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OLD VERSION (can be ignored):

Disease ID and Name OMIM:301310 Anemia, sideroblastic, and spinocerebellar ataxia ORPHA:2802 X-linked sideroblastic anemia and spinocerebellar ataxia

HPO ID and Name HP:0000716 Depression HP:0100543 Cognitive impairment HP:0001824 Weight loss HP:0100753 Schizophrenia HP:5200230 Maladaptive fear-related cognitions (could also be used in addition for the described schizophrenia) HP:0009127 Abnormality of the musculature of the limbs HP:0000980 Pallor HP:0000726 Dementia HP:0001272 Cerebellar atrophy HP:0001321 Cerebellar hypoplasia HP:0001250 Seizure (Epilepsy) HP:0000028 Cryptorchidism HP:0001992 Organic aciduria HP:0025373 Interictal EEG abnormality HP:0006999 Basal ganglia gliosis HP:0002363 Abnormal brainstem morphology HP:0012751 Abnormal basal ganglia MRI signal intensity HP:0012187 Increased erythrocyte protoporphyrin concentration HP:0004447 Poikilocytosis HP:0011273 Anisocytosis HP:0020081 Pappenheimer bodies HP:0032550 Howell-Jolly bodies HP:0034280 Target cells HP:0031020 Bone marrow hypercellularity HP:0012132 Erythroid hyperplasia HP:0001350 Slurred speech HP:0001336 Myoclonus HP:0003199 Decreased muscle mass HP:0001270 Motor delay HP:0002870 Obstructive sleep apnea HP:0001388 Joint laxity HP:0004322 Short stature HP:0001320 Cerebellar vermis hypoplasia HP:0100307 Cerebellar hemisphere hypoplasia HP:0001618 Dysphonia HP:0000602 Ophthalmoplegia HP:0002015 Dysphagia HP:0000717 Autism HP:0001315 Reduced tendon reflexes HP:0008897 Postnatal growth retardation HP:0000565 Esotropia HP:0006897 Abducens palsy HP:0001276 Hypertonia

Further information (Frequency, Onset, Pubmed-references, Comments) PMID: 26242992 Quote 1: The mental and neurological symptoms are varied in patients with described mutations in the ABCB7 gene. The depression, cognitive declines or intellectual disabilities and even schizophrenia were described for some patients Quote 2: As shown by MRI in the Buryat family case, the brain atrophy was mostly localized in the cerebellar hemispheres and the vermis. Quote 3: Magnetic resonance imaging (MRI) scans revealed hypoplasia of cerebellar hemispheres and vermis in affected males from the Buryat pedigree. For more infos see the attached 'Supplementary Information' document in the publication.

PMID: 21464130 Quote: Other reported symptoms include dysarthria, intention tremor, mild learning disability, and depression.

PMID: 20301496 Quote: Mild learning disability and depression are seen.

PMID: 11118249 Quote 1: Schizophrenia was diagnosed in his 20s and he has remained on phenothiazine medication since. Quote 2: Of note he had a mild anaemia and raised FEP concentrations. Also Pappenheimer bodies were visible on his blood film (fig 3), especially prominent in view of his splenectomy. Brain MRI showed a markedly atrophic cerebellum, with some atrophy of the pons and medulla (fig 4). Quote 3: Haematological investigations are shown in the table. Key abnormalities include a low mean corpuscular volume, a raised FEP concentration, Pappenheimer bodies on the blood film, and ring sideroblasts in the bone marrow. Brain MRI showed selective atrophy of the cerebellum, with the pons and medulla of normal size (fig 4). Quote 4: Haematological indices were normal except that she had Pappenheimer bodies on her blood film (table) Quote 5: He is thought to have a moderate dementia. Quote 6: He always had slurred speech.

See Table 'Haematological findings' in line 'Blood film' for: Pappenheimer bodies, Anisocytosis, Poikilocytosis, Targer cells and Howell-Jolly bodies

PMID: 11050011 Quote 1: From early infancy, the proband had mild postnatal growth retardation and substantially impaired gross motor and cognitive development. Quote 2: ..., and he attended a special school where he exhibited severe, static intellectual impairment. Quote 3: Computed tomography of the brain at age 18 showed striking, selective cerebellar hypoplasia, but no further action was taken until the proband was brought for examination at age 22 year with pallor and weight loss; sideroblastic anemia and nonprogressive cerebellar ataxia were diagnosed. Quote 4: Total erythrocyte protoporphyrin (EP) was markedly elevated in the proband to 25.7 μmol/L, with zinc EP comprising 65% of the total and free erythrocyte protoporphyrin (FEP) accounting for 35% (Table 2).

PMID: 34354969 Quote 1: In this case, he had new symptoms that had not been reported in other cases such as epilepsy and cryptorchidism. Quote 2: Decreased muscle tone in the proximal upper and lower limbs and normal muscle strength were found. Quote 3: The proband was a 5-year-old boy who was admitted to our hospital for recurrent seizure and growth retardation for 4 years. Quote 4: The patient's first generalized seizure occurred at 11 months of age. Quote 5: Other symptoms included growth retardation, dementia, intellectual impairment, and impaired gross motor and cognitive development. Two patients had mental disorder: P3 had schizophrenia and P13 was diagnosed with depression. P18 had epilepsy and cryptorchidism. Some patients had changed muscle tone and abnormal tendon reflexes and plantar responses. Quote 6: Brain MRI were performed in P2 and P3 at the age of 50 and showed atrophic cerebellum, and P3 had atrophy of the pons and medulla. P16 underwent computed tomography of the brain at age 18, and striking, selective cerebellar hypoplasia was found. Quote 7: Growth retardation, mental disorder, and intellectual impairment were also found in the patients. In this case, the patient was diagnosed with epilepsy in infancy and had cryptorchidism, which had not been described in other cases. Quote 8: Cerebral imaging of some patients showed atrophic cerebellum. Quote 9: The examination of urinary organic acids showed significantly increased 2-hydroxyisobutyric acid, glycolic acid, oxalic acid, phosphoric acid, and glyceric acid (Table 1). Quote 10: Interictal electroencephalogram was found with spikes and sharp waves over the bilateral frontal region, anterior midline region, and centrotemporal region during both the waking and sleeping periods (Figure 1). Quote 11: MRI showed lacunar infarction in the left basal ganglia with glial proliferation around and small tiny left transverse sinus, sigmoid sinus, and internal jugular vein (Figure 2). Quote 12: Bilateral cryptorchidism was detected by ultrasonography (Figure 3). Quote 13: Erythrocyte protoporphyrin of 8/8 patients and 4/6 carriers was significantly higher than the normal range. Microcytic, hypochromic red cells, abnormally shaped cells, pappenheimer bodies, and anisocytosis were commonly seen in blood films. Bone marrow examination were performed in four patients and two carriers, and all of them had ringed sideroblasts. (Table 4) Quote 14: Growth retardation, mental disorder, and intellectual impairment were also found in the patients. Quote 15: Scores of the Checklist for Autism in Toddlers-23 (CHAT-23) and the Clancy Autism Behavior Scale (CABS) were 20 and 15, respectively, both of which indicated he might have autism.

Myoclonus -> see Table 3 > Patient 13 > Column > 'Other symptoms' Howell-Jolly bodies -> see Table 4 > Patient 2 > Column > 'Blood film'

PMID: 4045952 Quote 1: Some heterozygous females have ring sideroblasts on bone marrow examination, a dimorphic peripheral blood smear, and raised serum free erythrocyte protoporphyrin. Quote 2: Peripheral blood smear showed microcytic, hypochromic red cells with anisocytosis and cigarshaped cells. Quote 3: At the age of 32 years he had a verbal IQ of 95 and a performance IQ of 82 on the WAIS-R. Quote 4: (Patient III.1) His peripheral smear showed microcytic, hypochromic red cells with marked poikilocytosis, shift to the left, and heavy stippling. Bone marrow examination showed hypercellularity with an E:G ratio of 3:1 and increased iron stores with 80% ring sideroblasts. Quote 5: (Patient B) Peripheral smear showed poikilocytosis with abnormally shaped cells. Bone marrow examination at one year of age showed an E:G (erythropoese:granulopoese) ratio of 3:1, normal myeloid precursors, abundant iron stores, and occasional ring sideroblasts. Quote 6: He had had surgery for accommodative esotropia.

PMID: 11843825 Quote: Pappenheimer bodies were seen in both affected brothers and were present in the mother albeit in fewer numbers of red cells (data not shown).

PMID: 17192393 Quote: ABCB7 is ubiquitous, and its deficiency may cause mitochondrial iron deposition and sensitivity to oxidative damage in most cells, but the ones most sensitive seem to be those of the basal ganglia whose degeneration may cause ataxia and movement disorders, similar to what occurs in Friedreich ataxia and Pank disease.

PMID: 22398176

https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2545 Quote: In the majority of cases magnetic resonance imaging (MRI) shows cerebellar atrophy/hypoplasia.

https://www.ncbi.nlm.nih.gov/clinvar/variation/208533/ I'm not sure if this is actually a real case or just a 'copy' or a 'review' of another publication. It is up to you to decide whether or not to include it. If the case is not included, then there are only 18 cases/patients and not 19 as indicated below. And some HPO-terms would then probably have to be removed like "Decreased muscle mass", "Obstructive sleep apnea" and "Joint laxity" and for some, the counter would then have to be reduced. Quote: Clinical Features: Muscular hypotonia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Joint laxity (present) , Strabismus (present) , Short stature (present) , Obstructive sleep apnea syndrome (present) , Decreased muscle mass (present) , Motor delay (present)

As for the frequency of symptoms/phenotypes, I can't say much. However, I would guess that depression, cognitive impairment, dementia, schizophrenia, abnormal fear/anxiety-related behavior, cerebellar atrophy and cerebellar hypoplasia are the most frequent (very frequent) phenotypes. While symptoms/phenotypes such as weight loss, abnormality of the limb muscles and pallor (due to the involvement of iron in this disease) are 'only' frequent. And symptoms such as seizures/epilepsy and cryptorchidism are only occasional.

EDIT: (Note: I have just learned that the frequency in this format is preferred. Considering the fact that less than 20 people worldwide are affected by this disease, I have estimated the frequency of these symptoms based on the frequency of their mention in the publications. I have also taken into account the HPO terms that I have just added. If there are any uncertainties, just let me know.)

Phenotype frequency spreadsheet: https://docs.google.com/spreadsheets/d/1BIhd_1CL_RknMOlR8pChCx8f1u4F_mvXgtzC_iAPiAQ/edit?usp=sharing

Frequency: HP:0000716 Depression (1/19) HP:0100543 Cognitive impairment (2/19) HP:0001824 Weight loss (1 or 2/19) (see spreadsheet for more details) HP:0100753 Schizophrenia (1/19) HP:5200230 Maladaptive fear-related cognitions (1/19) HP:0009127 Abnormality of the musculature of the limbs (1/19) HP:0000980 Pallor (1 or 2/19) (see spreadsheet for more details) HP:0000726 Dementia (1/19) HP:0001272 Cerebellar atrophy (9/19) HP:0001321 Cerebellar hypoplasia (8 or 9/19) (see spreadsheet for more details) HP:0001250 Seizure (Epilepsy) (1/19) HP:0000028 Cryptorchidism (1/19) HP:0001992 Organic aciduria (1/19) HP:0025373 Interictal EEG abnormality (1/19) HP:0006999 Basal ganglia gliosis (1/19) HP:0002363 Abnormal brainstem morphology (2/19) HP:0012751 Abnormal basal ganglia MRI signal intensity (1/19) HP:0012187 Increased erythrocyte protoporphyrin concentration (9/19) HP:0004447 Poikilocytosis (4/19) HP:0011273 Anisocytosis (3/19) HP:0020081 Pappenheimer bodies (3/19) HP:0032550 Howell-Jolly bodies (1/19) HP:0034280 Target cells (1/19) HP:0031020 Bone marrow hypercellularity (1/19) HP:0012132 Erythroid hyperplasia (2/19) HP:0001350 Slurred speech (1/19) HP:0001336 Myoclonus (1/19) HP:0003199 Decreased muscle mass (1/19) HP:0001270 Motor delay (4/19) HP:0002870 Obstructive sleep apnea (1/19) HP:0001388 Joint laxity (1/19) HP:0004322 Short stature (3/19) HP:0001320 Cerebellar vermis hypoplasia (7/19) HP:0100307 Cerebellar hemisphere hypoplasia (7/19) HP:0001618 Dysphonia (2/19) HP:0000602 Ophthalmoplegia (5/19) HP:0002015 Dysphagia (1/19) HP:0000717 Autism (1/19) HP:0001315 Reduced tendon reflexes (4/19) HP:0008897 Postnatal growth retardation (3/19) HP:0000565 Esotropia (1/19) HP:0006897 Abducens palsy (1/19) HP:0001276 Hypertonia (1/19)

[D0ctorNo]

Would it be possible to include these phenotypes/hpo-terms in the January HPO update? That would be great and incredibly helpful. @pnrobinson

[pnrobinson]

Thanks for all of this information. Could I ask which PMIDs the frequency information is derived from?

[D0ctorNo]

Due to the fact that only about 20 people worldwide are affected by this disease and therefore no meaningful information about the frequency of the symptoms is available yet, I have estimated the frequency based on the intensity/severity of the symptoms/phenotypes and the function/task of the protein. The frequency is therefore based solely on my subjective assessment. If in doubt, you can omit the frequency until more reliable data is available. @pnrobinson

[pnrobinson]

I see! Our strategy has been to just write down what we know, even if it is not a lot of data, e.g., 1/3. This can be combined later on with other datasources, but it is difficult to combine if we start with an estimate. What if we have a look at the publications you list and extract as much as we can?

[D0ctorNo]

Sure. Whatever you think is right. I would just follow your guidelines. @pnrobinson

[D0ctorNo]

I just created a spreadsheet with the frequency of phenotypes. I also updated and added some phenotypes while submitting the changes in the original post above. I have written a few notes under the spreadsheet. Take a look at it and check whether it is correct so far. I am sorry that it has taken a little longer than expected but if there are any uncertainties, problems or questions please do not hesitate to contact me. @pnrobinson

Phenotype frequency spreadsheet: https://docs.google.com/spreadsheets/d/1BIhd_1CL_RknMOlR8pChCx8f1u4F_mvXgtzC_iAPiAQ/edit?usp=sharing

[D0ctorNo]

any updates/news on this? I've seen that this issue is not part of the new 2024-11-01 update. @pnrobinson

[D0ctorNo]

In case the old post was a bit confusing, I have created a new and hopefully better version and corrected many errors in the process. I hope all is well now and apologise for any inconvenience this may have caused and hope that this improvement will make it into the next update. As always, if there are any uncertainties or problems please do not hesitate to contact me.

@pnrobinson

[D0ctorNo]

Dear Mr. Robinson, I know that you are very busy at the moment and are way behind schedule. But it would be of utmost importance that these HPO terms are added to the disease as soon as possible. I would therefore kindly and with the greatest indulgence ask you to add them by the next HPO-update in April. This would save (us) a lot of trouble and possible further damage. I would therefore very much appreciate it if you would make an effort to do so. Thank you very much. @pnrobinson

[pnrobinson]

@D0ctorNo

Sorry, I have moved from the US back to Germany last year and things have been extremely busy. We have been inviting colleagues who contribute annotation data to join a data manuscript we are preparing. perhaps we can do this for XLSA-A shortly. There are some columns that appear to combine data from multiple publications in your spreadsheet? https://github.com/monarch-initiative/phenopacket-store/tree/main/notebooks We can then transfer this to the main HPO dataset if you would like to get in contact my email is here https://robinsongroup.github.io/contact/

[pnrobinson]

@D0ctorNo I am going to start to annotate these papers using phenopacket format, but I think we first need a term

Increased ringed sideroblasts in the bone marrow def: Increased count of ring sideroblasts (RS) in the bone marrow. RS are erythroid precursors with iron laden mitochondria forming a perinuclear ring. The presence of 15 percent of more RS indicates a diagnosis of myelodysplastic neoplasm with ring sideroblasts (MDS-RS), but RS can be observed in other clinical settings, including non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations.

Comment: Perls’ stain is a cytochemical reaction performed on bone marrow (BM) smears. It remains the gold standard method for the detection of iron overload, and its main purpose is to detect the presence of ring sideroblasts (RS). RS are pathological erythroblasts with an excess of iron-loaded mitochondria. They have a minimum of five blue granules covering at least one-third of the nuclear circumference. Ring sideroblasts should not be confused with ferritin sideroblasts. After Perls’ stain, ferritin sideroblasts, corresponding to normal erythroblasts, show few blue granules scattered in the cytoplasm, which represent endosomes filled with excess iron not used for heme synthesis. While the iron in ferritin sideroblasts is stored in cytosolic ferritin, the iron in ring sideroblasts is stored in mitochondrial ferritin.

PMID:35885655 PMID:4045952

[D0ctorNo]

@pnrobinson Has this not already been done a few months ago (I think in March)? This disease is caused by a mutation in the ABCB7 gene. Take a look: https://github.com/monarch-initiative/phenopacket-store/tree/main/notebooks/ABCB7

But of course you can still add or create new HPO-terms for this disease.

[pnrobinson]

You're right, but I think I only made a start with the work in March. I think we need to debundle the sideroblastic anemia term, which means anemia PLUS presence of ring sideroblasts in the bone marrow, i.e., two distinct phenotypic features. I am going to do that and then annotate a few more of the publications in the next month and then will close this.

[D0ctorNo]

@pnrobinson That sounds great. While you are doing this, you could also take note of the "updated" HPO-terms that the Orphanet team extracted from these six PubMed cases in February this year. As soon as orphadata updates the xml file (en_product4.xml) in July, these HPO-terms will soon be part of the HPO: https://www.orpha.net/en/disease/sign/2802

You can see the differences if you compare the "old" en_product4.xml file from december 2023 with the new HPO-terms on the orphanet website mentioned above.

[D0ctorNo]

@pnrobinson I think it would not be a bad idea to combine all genes (398 genes) that are somehow involved in iron metabolism into one HPO term. There is already an HPO term called "Abnormality of iron homeostasis" with 28 linked genes. Maybe it is possible to adapt them somehow and link the 398 genes from this publication (PMID: 30095136) to this phenotype or even create an entire new phenotype/HPO-term for this. I have already extracted all genes from this publication (Supplementary data) and put them into a pastebin.

The human-iron-proteom: https://doi.org/10.1039/c8mt00146d Pastebin file with all extracted genes from the publication's supplementary files mentioned above: https://pastebin.com/c3vdXBWi Already existing HPO-term: HP:0011031 Abnormality of iron homeostasis

Of course, this is just a thought on my part. I'd like to know what you think about this.

[pnrobinson]

@D0ctorNo as far as I can see most of the iron genes are involved in the biology of iron but are not related to Mendelian diseases, which is the scope of these annotations? The place for biology annotations would probably be Gene Ontology.

[D0ctorNo]

@pnrobinson There are a number of neurological/psychological disorders that can be attributed to a malfunction of iron metabolism (e.g. ABCB7). This is probably due to the fact that the basal ganglia have the highest concentration of iron in the brain and therefore show a range of neurological and psychological symptoms when iron metabolism is not functioning properly. It would therefore be useful to have an HPO term that covers all genes involved in this process.

[pnrobinson]

The HPO does not cover pathophysiology, and this is out of scope. The HPO is designed to cover observable phenotypic features, e.g., a concentration measurement.