Neuropathy, Hereditary Motor And Sensory, Type Vib, With Optic Atrophy

A number sign (#) is used with this entry because of evidence that hereditary motor and sensory neuropathy type VIB with optic atrophy (HMSN6B) is caused by homozygous or compound heterozygous mutation in the SLC25A46 gene (610826) on chromosome 5q22.

Description

Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements, such as ataxia, dysmetria, and myoclonus. The most severely affected patients are hypotonic at birth and die in infancy (summary by Abrams et al., 2015 and Wan et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).

Clinical Features

Abrams et al. (2015) reported 8 patients from 4 unrelated families of various ethnic origins with optic atrophy and peripheral neuropathy manifest as axonal Charcot-Marie-Tooth disease. There was extreme phenotypic variability in age at onset, additional features, and severity. Two sibs from the United Kingdom presented with optic atrophy and progressive visual loss at ages 5 and 8 years, but did not develop peripheral neuropathy until their forties. Features included stiffness and distal sensory impairment of the lower limbs associated with hyperreflexia and extensor plantar responses. Nerve conduction studies showed unrecordable sensory nerve action potentials, decreased compound muscle action potentials, and slowed motor nerve conduction velocities, all consistent with an axonal motor and sensory polyneuropathy. Brain imaging and muscle biopsy were unremarkable. A 51-year-old man from Sardinia presented with progressive visual impairment at age 2 years. In his second decade, he developed difficulty walking associated with distal muscle atrophy as well as speech difficulties. Physical examination showed optic atrophy, mild deafness, cerebellar dysfunction with nystagmus and dysmetria, ataxic and steppage gait, hyperreflexia with absent ankle reflexes, and pes cavus. Electromyography showed axonal sensorimotor neuropathy, and brain imaging showed diffuse brain and cerebellar atrophy with cerebellar white matter abnormalities, chiasm atrophy, and calcifications in the basal ganglia. Three sibs from a consanguineous Palestinian family had normal early development in the first 1 to 2 years of life, but then showed developmental delay and visual loss with optic nerve pallor, loss of motor skills, hypertonia, hyperreflexia, and ataxia, and were wheelchair-bound by late childhood. Muscle and nerve biopsy of 1 patient showed autonomic denervation with onion bulb morphology and rare axonal demyelination and degeneration. A deceased sib was similarly affected. In the fourth family, a girl from the United States had hypotonia and contractures at birth, as well as dysmorphic features, including bitemporal narrowing, upturned nose with bulbous tip, tented upper lip, narrow palate, flat midface, inverted nipples, and tapered fingers. She also had optic atrophy. Brain imaging showed progressive cerebellar and brainstem atrophy. She died at age 15 weeks.

Charlesworth et al. (2016) reported 2 brothers, born of consanguineous Pakistani parents, with a complicated form of axonal sensorimotor neuropathy. The proband presented with balance problems in infancy. On physical examination at age 15, he had prominent action-induced myoclonus, cerebellar ataxia, nystagmus, dysmetria, tremor, and mild spasticity. He also had profound visual loss with rod-cone dysfunction, exotropia, and difficulties initiating saccades. He had scoliosis and neuropathy-induced trophic changes, and was wheelchair-bound. Brain imaging showed cerebellar atrophy and T2-weighted hyperintensities and cavitations in the cerebellum. Cognition was normal. His 20-year-old brother was similarly, though more mildly, affected.

Clinical Variability

Wan et al. (2016) reported 4 infants from 2 unrelated consanguineous families who died soon after birth with a profound neurodevelopmental disorder associated with congenital pontocerebellar hypoplasia. Three of the 4 pregnancies were noted to be complicated by polyhydramnios. The patients presented at birth with severe hypotonia and respiratory distress necessitating ventilatory support, areflexia, and occasional myoclonic jerks. EEG in 2 patients showed generalized slowing, but no epileptiform activity, whereas 1 patient developed seizures at 3 weeks of age. Additional features included optic atrophy and severe global developmental delay. EMG and nerve conduction studies in 2 patients were consistent with an axonal sensorimotor neuropathy. Brain imaging of all patients showed a small cerebellum and brainstem, consistent with pontocerebellar hypoplasia. Mitochondrial respiratory chain enzyme testing in 2 patients was normal. All patients died between 2 weeks and 3 months of age. Wan et al. (2016) noted the phenotypic similarities to a female infant from the United States with pontocerebellar atrophy who died at age 15 weeks; this infant was previously reported by Abrams et al. (2015).

Janer et al. (2016) reported a female infant, born of consanguineous French Canadian parents, with a lethal form of HMSN6B. She developed a convulsion at 4 hours of age, which did not recur. In the first months of life, she showed irritability, feeding and swallowing difficulties, failure to thrive, and delayed psychomotor development. At age 13.5 months, she presented with a febrile seizure and respiratory failure. Brain imaging at that time showed lesions in the cerebellar white matter, cerebellar peduncles, and brainstem, as well as in the globi pallidi, consistent with a clinical diagnosis of Leigh syndrome. Ophthalmologic examination showed optic atrophy. She had mild spasticity and hyperreflexia; EMG and nerve conduction studies were not performed, but muscle biopsy showed neurogenic atrophy. She died soon thereafter. Laboratory studies showed intermittent lactic acidosis, with mildly increased lactate and pyruvate in the CSF.

Inheritance

The transmission pattern of HMSN6B in the families reported by Abrams et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 4 families with HMSN6B, Abrams et al. (2015) identified homozygous or compound heterozygous mutations in the SLC25A46 gene (610826.0001-610826.0006). Mutations in the first 3 families were found by whole-exome sequencing; mutation in the fourth family was found by Sanger sequencing of the SLC25A46 gene in cases with a similar phenotype. Functional studies of the variants were not performed. Fibroblasts from 1 patient showed a hyperfilamentous and interconnected mitochondrial network compared to controls, as well as decreased oxygen consumption rate and a glycolytic shift in metabolism. These findings were consistent with decreased mitochondrial fission.

In 4 sibs from 2 unrelated consanguineous families with a severe form of HMSN6B resulting in death in infancy, Wan et al. (2016) identified 2 different homozygous loss-of-function mutations in the SLC25A46 gene (610826.0007 and 610826.0008). Although 1 of the mutations was a missense mutation (L341P; 610826.0007), in vitro studies showed that it resulted in markedly decreased amounts of protein, suggesting that the clinical severity is inversely correlated with relative stability of the mutant protein.

In 2 brothers, born of consanguineous Pakistani parents, with HMSN6B, Charlesworth et al. (2016) identified a homozygous missense mutation in the SLC25A46 gene (L138R; 610826.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In a girl, born of consanguineous French Canadian parents, with infantile lethal HMSN6B, Janer et al. (2016) identified a homozygous missense mutation in the SLC25A46 gene (T142I; 610826.0010). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutant protein was virtually undetectable in patient fibroblasts, which showed mitochondrial hyperfusion, alterations in endoplasmic reticulum morphology, impaired cellular respiration, and premature cellular senescence.

Genotype/Phenotype Correlations

SLC25A46 mutations that result in decreased levels of the mutant protein cause a lethal infantile form of HMSN6B associated with neurodegeneration and pontocerebellar hypoplasia: see 610826.0004-610826.0005 and Abrams et al. (2015); 610826.0007 and 610826.0008 and Wan et al. (2016); and 610826.0010 and Janer et al. (2016).

Animal Model

In zebrafish, Abrams et al. (2015) found expression of slc25a46 in retinal ganglion cells and their corresponding neuronal projections in axons of the optic nerve and dendrites of the inner plexiform layer. Morpholino knockdown of the gene resulted in fewer retinal ganglion cell axons that reached the tectum, as well as impairment of these dendrites. Morpholino knockouts had a curly tail morphology and impaired swimming, suggesting dysfunction of neural circuits, and spinal motor neurons had shortened axon tracts due to degeneration of neuronal processes. Mitochondria in the degenerating motor neurons showed incomplete fission, abnormal aggregation, and abnormal cell localization compared to wildtype.

Wan et al. (2016) found that morpholino knockdown of the slc25a46 gene in zebrafish embryos resulted in a dose-dependent phenotype of brain maldevelopment in the midbrain and hindbrain, as well as loss of spinal motor neurons. Dissociated neurons from mutant animals showed elongated and immotile mitochondria compared to controls, suggesting impaired fission/fusion dynamics.