The syndrome of deafness‐dystonia: Clinical and genetic heterogeneity

The syndrome of deafness‐dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr‐Tranebjaerg syndrome, Woodhouse‐Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness‐dystonia syndrome. We evaluated 20 patients with deafness‐dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic‐ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr‐Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse‐Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work‐up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory‐neural deafness always preceded dystonia. Two clinical patterns of deafness‐dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness‐dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions. © 2013 Movement Disorder Society     

Gonadal mosaicism as a rare cause of autosomal recessive inheritance

Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal‐dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes.     

GLI3‐related polydactyly: a review

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3‐related polydactyly are discussed first. This is followed by a detailed review of the genotype–phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3‐related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV‐Greig‐acrocallosal spectrum, postaxial polydactyly types A/B, Pallister–Hall syndrome (PHS), and oral‐facial‐digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term ‘Forme Fruste’ preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.     

Pellagra‐like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit

An extremely rare pellagra‐like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra‐like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet‐induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.     

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal‐recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1‐R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1‐deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1‐associated ID disorders.