Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442204007379.pdf

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.

Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D

Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA (ref. 2), has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana3 and in a Lebanese family4. We identified this gene (USH1C), encoding a PDZ-domain–containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.

A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C.

Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13–21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration1,2. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells.

Dominant and recessive deafness caused by mutations of a novel gene, TMC1 , required for cochlear hair-cell function

Current status of newborn screening worldwide: 2015

The mother child dyad—Nutritional aspects. Edited by L f Hambraeus and Stig SjolinHambraeus and Stig Sjolin: Almquist and Wiksell International, Stockholm, Sweden 1979 pages 155, Price SW kr 120

Many syndromes can be diagnosed based on their gestalt appearance. Silvery hair is a cardinal sign which can suggest the correct diagnosis. If you have not diagnosed this case based on gestalt, read on! A 3-y-old boy, first born of a third-degree consanguineous marriage, was referred for the gradual loss of previously attained milestones for three months before evaluation. He had hypopigmented silvery hair from birth, which was not familial. Presently, in the absence of a precipitating cause like a seizure, trauma or recent vaccination, he started to fall while walking, became ataxic, irritable, and gradually lost speech and the ability to stand at the age of 2 y and 9 mo. He could sit with support and speak 1–2 words with meaning. There was a history of recurrent upper respiratory tract infections, for which he required hospitalization on two occasions. Examination revealed an irritable and apathic boy who was not interested in his surroundings. General physical examinat ion showed si lvery grey hai r on the scalp and eyebrows, (Fig. 1a) and hypopigmented hair on rest of the body. Anthropometric measurements were within normal limits. On abdominal examination, there was an enlarged firm liver, with a span of 7 cm. The spleen was palpable 3 cm below the costal margin. Nervous system examination showed truncal ataxia, mildly increased tone and easily elicitable reflexes. With the background of consanguinity, neuro-regression and silvery hair, a differential diagnosis consisting of Griscelli syndrome [1], Chediak Higashi syndrome [2], Hermansky Pudlak syndrome [3], Menke disease, Vici syndrome (Online Mendelian Inheritance in Man, OMIM# 242840), Cross syndrome (OMIM# 257800), MAPBP-interacting protein-related immunodeficiency (OMIM # 610798) were considered. Complete blood count showed pancytopenia (Hemoglobin: 7.2 g/dl, total leukocyte count 2388/μL, Platelet count 80,000/ μL, and absolute lymphocyte count 1000/μL). Deficiency of antibodies was observed: IgG 288 mg/dl (453–916) and IgM levels: 20 mg/dl (21–146). Microscopic study of hair revealed pigmentation and clumping of melanosomes in the outer hair sheath and shaft (Fig. 1c). MRI brain showed white matter changes in bilateral cerebellar hemispheres (Fig. 1b). These findings were consistent with the clinical diagnosis of Griscelli syndrome (GS). Due to locus heterogeneity of this disorder, the study of clinical exome was ordered, which identified a homozygous pathogenic variant in the RAB27A gene (c.239 + 1G >T; ENST00000396307) confirming the diagnosis of GS type II. This mutation has been previously described [1]. Griscelli syndrome is of three types based on the gene involved and the clinical phenotype. GS type 1 (OMIM# 214450) has mutations in the MYO5A gene with predominant neurological involvement. GS type 2 (OMIM# 607624) involves the RAB27 gene and is character ised by hypopigmentation, immunodeficiency and neurological involvement in some cases [1]. In this patient, the presentation of neurological symptoms was subacute, and there was no clearly-defined accelerated phase of the disease. It constitutes worsening of neurological symptoms and regression of milestones [1]. GS type 3 (OMIM# 609227) consists of pathogenic variants in the MLPH gene, or rarely MYO5A and is clinically milder with only hypopigmented hair. The presence of silvery hair is the most important diagnostic feature for Griscelli syndrome, and its presence, even in an asymptomatic infant deserves further workup. It is important to identify this disorder early as hematopoietic stem cell transplantation before the appearance of neurologic involvement is potentially curative [4].

Neuro-Regression in a Child with Silvery Hair

The results of the 1981 census of India are briefly reviewed. Some implications concerning the literacy program population policy and the health program are discussed. (ANNOTATION)

Census of India, 1981 and implications for health planning.

/pdf/new-bacterial-vaccines-for-acute-respiratory-infections-bch4oay3h8.pdf

Ishwar C. Verma

Papers

The mother child dyad—Nutritional aspects. Edited by L f Hambraeus and Stig SjolinHambraeus and Stig Sjolin: Almquist and Wiksell International, Stockholm, Sweden 1979 pages 155, Price SW kr 120

Neuro-Regression in a Child with Silvery Hair

Census of India, 1981 and implications for health planning.

New bacterial vaccines for acute respiratory infections.

Perspectives in acute intermittent porphyria.