Novel Mutations in FA2H-Associated Neurodegeneration: An Underrecognized Condition?

Hereditary spastic paraplegias and related genetically heterogeneous disorders may be difficult to distinguish clinically. The FA2H gene has been associated with autosomal recessive neurodegenerative phenotypes encompassing spastic paraplegia with or without dystonia, and demyelinating leukodystrophy. To date, few individuals with mutations in the FA2H gene have been described. We report a 5-year-old girl of mixed Filipino and Vietnamese origin who presented with progressive lower limb spasticity and periventricular leukomalacia. The clinical diagnosis of FA2H-associated neurodegeneration was confirmed on the basis of 2 novel mutations in compound heterozygosity in the FA2H gene (p.S70L/p.P323L). This family highlights that FA2H-associated disorders may be underrecognized in children with neurodegeneration of many different ethnicities. Magnetic resonance imaging features play an important role as diagnostic clues in this and other hereditary spastic paraplegias. The consideration of this diagnosis is essential in providing families with important information on prognosis, as well as accurate genetic counseling.

X-linked cataract and Nance-Horan syndrome are allelic disorders.

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.