Measuring disease progression in giant axonal neuropathy: implications for clinical trial design.

As part of a natural history study of giant axonal neuropathy, we hypothesized that the Friedreich Ataxia Rating Scale and the Gross Motor Function Measure would show a significant change over 6 months, reflecting subjects' decline in motor function. The Friedreich Ataxia Rating Scale was performed on 11 subjects and the Gross Motor Function Measure was performed on 10 subjects twice with a six-month interval. A paired two-tailed t-test was used to assess the difference in each subject's score. Significant changes were found over six months of 11.7 ± 11.0 (P = 0.006) for the Friedreich Ataxia Rating Scale and -10.0 ± 13.5 (P = 0.043) for the Gross Motor Function Measure, reflecting subjects' decline in motor function on examination and by report. These standardized assessments of clinical function are the first to be validated in giant axonal neuropathy and will be used in an upcoming gene therapy clinical trial.

Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish.

INTRODUCTION: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2-3 months of life. METHODS: We describe an Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing. RESULTS: Direct sequencing revealed that he is homozygous for a pathogenic nonsense variant c.323C>G (p.S108X) in exon 9 of the TNNT1 gene. CONCLUSIONS: This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy-causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry.

The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy.

Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p=0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot-Marie-Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot-Marie-Tooth Disease type 2.