Neuropathy, Hereditary Motor And Sensory, Okinawa Type

A number sign (#) is used with this entry because Okinawa hereditary motor and sensory neuropathy (HMSNO) is caused by heterozygous mutation in the TFG gene (602498) on chromosome 3q.

Description

HMSNO is an autosomal dominant neurodegenerative disorder characterized by young adult onset of proximal or distal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis (ALS; 105400) (summary by Ishiura et al., 2012).

Clinical Features

Takashima et al. (1997) reported an autosomal dominant form of hereditary motor and sensory neuropathy with dominant proximal involvement. There were 23 patients from 8 families, all from Okinawa, Japan. The characteristics of the disorder included adult-onset proximal neurogenic atrophy, sensory involvement, painful muscle cramps, fasciculations, areflexia, and high incidences of elevated creatine kinase levels, hyperlipidemia, and diabetes mellitus. The clinical features resembled those of Kennedy syndrome (313200), although the mode of inheritance was different (autosomal dominant, not X-linked), and had been reported only in Okinawa, Japan. Neuropathologic analysis revealed decreased numbers of anterior horn cells and marked loss of myelinated fibers in the posterior funiculus.

Maeda et al. (2007) reported 2 large families from a small mountain village in the Kansai area of mainland Japan with an autosomal dominant phenotype similar to HMSN-P. The families consisted of 5 to 6 generations with a total of at least 40 affected individuals. The average age at onset was 37.5 years. Features included gradual progression of proximal muscle weakness and atrophy, painful muscle cramps, fasciculations, areflexia, and distal sensory loss. Pathology showed loss of axons in the peripheral nerves, as well as loss of anterior horn and dorsal root ganglion cells. Fujita et al. (2011) reported the neuropathologic findings of 1 of the patients reported by Maeda et al. (2007) who died of pneumonia at age 67 years. The disorder in this patient had progressed, and he was bedridden with bulbar weakness and dysphagia. He also had extensor plantar responses, areflexia, and distal sensory impairment. There was marked atrophy of the spinal cord roots, neuronal loss and gliosis in brainstem nuclei, severe neuronal loss in the anterior horns of the spinal cord, and loss of myelinated fibers in the corticospinal and spinocerebellar tracts and posterior column. The sural nerve showed decreased numbers of myelinated fibers. Immunohistochemistry revealed ubiquitin- and optineurin (OPTN; 602432)-positive neuronal inclusions. However, TDP43 (TARDBP; 605078)-positive inclusions were not observed. The findings indicated that the disorder has features in common with motor neuron diseases, such as spinal muscular atrophy and ALS, and Fujita et al. (2011) proposed that it be considered a familial motor neuron disease with sensory neuronopathy rather than a form of HMSN.

Maeda et al. (2007) reported 3 adult brothers with HMSNO. They lived in Brazil, but their parents were from Okinawa, Japan. Each presented in the early forties with proximal muscle weakness affecting the upper and lower limbs, muscle cramps, and fasciculations. Although only 1 reported distal sensory impairment, all had decreased reflexes and decreased sensory nerve action potentials. EMG showed neurogenic changes, and serum creatine kinase was increased. One of the patients had been diagnosed with spinal muscular atrophy, and Maeda et al. (2007) noted that the phenotype also resembled ALS. Since individuals have emigrated from Okinawa to South America since 1908, neurologists in such places should be aware of this hereditary neuropathy.

Patroclo et al. (2009) reported 4 Brazilian brothers with HMSNO. Their grandparents had immigrated to Brazil from Okinawa, Japan. All had onset after age 30 years of muscle cramps and weakness affecting the upper and lower proximal muscles. There was slow progression, resulting in muscular atrophy of affected muscles. Other features included areflexia, distal sensory impairment, myotonia in the hands, fasciculations, and dysphagia. Two patients were wheelchair-bound in their late fifties. EMG showed neurogenic changes, and all had electrophysiologic evidence of an axonal motor and sensory polyneuropathy. Laboratory studies showed increased serum creatine kinase and variable dyslipidemia. Sural nerve biopsy of 2 patients showed reduction of nerve fibers, focal thickening of the myelin sheath, and abnormal mitochondria. Muscle biopsy of 1 patient showed neurogenic atrophy. Their deceased father was reportedly affected, consistent with autosomal dominant inheritance.

Ishiura et al. (2012) reported 2 new families from Okinawa, Japan, with HMSNO. Affected individuals had features similar to those reported by Takashima et al. (1997) and Maeda et al. (2007). The initial stage of the disorder was characterized by painful muscle cramps and fasciculations. Although some patients reported the painful cramps in their twenties, most had onset of motor weakness in the early forties. There was slowly progressive, predominantly proximal weakness and atrophy with diminished tendon reflexes in the lower extremities. Sensory impairment was generally mild. Laboratory studies showed mildly increased serum creatine kinase, and electrophysiologic studies showed a decreased number of motor units with abundant positive sharp waves, fibrillation, and fasciculation potentials. Sensory-nerve action potentials of the sural nerve were lost in the later stage of the disease. Neuropathologic examination of 1 patient (Fujita et al., 2011) showed TFG-immunopositive inclusion bodies in the motor neurons of the facial, hypoglossal, and abducens nuclei, and the spinal cord, as well as in the sensory neurons of the dorsal root ganglia. Inclusions were not found in glial cells. The TFG-immunopositive inclusions colocalized with ubiquitin deposition. In addition, phosphorylated TDP43-positive inclusions were identified in some motor and sensory neurons in the spinal cord; some inclusions were positive for both TFG and TDP43. There was also fragmentation of the Golgi apparatus in patient motor neurons.

Lee et al. (2013) reported a large Korean family with autosomal dominant HMSNO. Affected individuals had adult onset (range, 27-48 years) of proximal muscle weakness, with cramping and fasciculations, and distal sensory impairment. Some of the patients had hand tremor early in the disease course, and MRI showed fatty infiltration in proximal muscles of the lower limbs. Laboratory studies showed hyperlipidemia and mildly increased serum creatine kinase. Sural nerve biopsy showed absence of large myelinated fibers, irregular thickness of myelin, and regenerating axonal clusters. Endoneural blood vessels of 2 patients showed swollen vesicular endothelial cells and narrowed lumens. Bulbar signs and pes cavus were not present.

Tsai et al. (2014) reported a large multigeneration Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy clinically consistent with Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A1, 118210) in which common CMT2-implicated genes had been excluded. The age at onset ranged from 28 to 40 years, and all patients presented with slowly progressive symmetrical muscle atrophy and weakness predominantly affecting the distal parts of the limbs and causing gait difficulties in most patients. There was also hypo- or areflexia of the lower limbs and mild distal sensory impairment. Sural nerve biopsy of 1 patient showed a loss of large myelinated nerve fibers with relatively preserved median and small myelinated nerve fibers and no signs of demyelination. Exome sequencing identified a heterozygous missense mutation in the TFG gene (G269V; 602498.0003).

Mapping

Takashima et al. (1997) mapped the disease locus to a 41-cM region on chromosome 3p14.1-q13 with a maximum lod score of 4.04 and 3.10 for D3S1284 and D3S1591, respectively. The presence of a common allele of marker D3S1591 and the geographic specificity of the disease suggested linkage disequilibrium and a single founder. To further narrow the localization, Takashima et al. (1999) used the linkage disequilibrium method. They showed that the locus maps to a 3.1-cM interval bracketed by D3S1591 and D3S1281. Using 9 marker loci jointly, they demonstrated a lod score of 4.93. Consequently, they concluded that the locus almost certainly lies on chromosome 3q13.1.

By linkage analysis of 2 large families from Kansai, Japan, Maeda et al. (2007) identified a candidate region on chromosome 3q13.1 (maximum 2-point lod score of 8.44) that overlapped with the locus identified by Takashima et al. (1999). The findings indicated that the causative gene likely resides in a 7.3-Mb interval between D3S1488i and D3S1083i. The disease haplotype shared among all affected members of the Kansai kindreds differed from that of the Okinawa kindred, suggesting allelic heterogeneity. Kansai is located about 1,200 km from Okinawa, and there is no record of migration or affinal connection between the 2 areas.

Molecular Genetics

In affected members of 4 Japanese families with proximal hereditary motor and sensory neuropathy, Ishiura et al. (2012) identified a heterozygous mutation in the TFG gene (P285L; 602498.0001). Two of the families were from the Kansai region (Maeda et al., 2007) and 2 were from Okinawa. Haplotype analysis suggested 2 independent origins of the mutation. The mutation was found by exome capture of the candidate region identified by linkage analysis. Expression of the mutant TFG protein resulted in mislocalization and TDP43-inclusion-body formation in cultured cells. These findings suggested a pathogenic link to ALS, in which TDP43 inclusions are found, and suggested that alteration of vesicle trafficking or RNA-mediated mechanisms might be involved in motor neuron degeneration in HMSNO.

Lee et al. (2013) identified a heterozygous P285L mutation in the TFG gene in affected members of a Korean family with HMSNO. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases. TFG levels in patient peripheral nerves were similar to controls.

In affected members of a large Taiwanese family with adult-onset motor and sensory axonal neuropathy, Tsai et al. (2014) identified a heterozygous missense mutation in the TFG gene (G269V; 602498.0003). The G269V mutant protein formed intracellular insoluble aggregates and colocalized with wildtype TFG, thus depleting soluble functional wildtype TFG. The large cytoplasmic G269V aggregates did not stain with TDP43 (605078). Knockdown of TFG using siRNA significantly reduced protein secretion from the endoplasmic reticulum (ER) and reduced cell viability, which could be rescued by wildtype TFG, but not by G269V TFG. The findings suggested that defects in the protein secretory pathways can cause dysfunction of the peripheral nervous system.