A number sign (#) is used with this entry because of evidence that autosomal recessive axonal Charcot-Marie-Tooth neuropathy type 2EE (CMT2EE) is caused by homozygous mutation in the MPV17 gene (137960) on chromosome 2p23.

Biallelic mutation in the MPV17 gene can also cause mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), a much more severe disorder with brain and liver involvement that usually leads to early death.

Charcot-Marie-Tooth disease type 2EE (CMT2EE) is an autosomal recessive sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs and is slowly progressive, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. There is significant distal muscle weakness and atrophy, usually with foot or hand deformities. Skeletal muscle biopsy shows findings of disturbed mitochondrial maintenance. Cognition is unaffected, and chronic liver disease is absent (summary by Baumann et al., 2019).

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Blakely et al. (2012) reported a 21-year-old Pakistani man with onset of slowly progressive distal muscle weakness and atrophy mainly affecting the lower limbs at age 14 years. At the same time, he had distal numbness and subjective coldness of the lower limbs up to the knees. Features included foot drop, difficulty walking with the need for orthotics, clawed toes, and absent reflexes. He had no significant cognitive impairment, and brain imaging showed diffuse hyperintense T2-weighed signals in the cerebral white matter. He had mild liver involvement manifest as transient hepatitis A infection as a child, mild hepatomegaly, mildly abnormal liver enzymes, and mild steatosis and fibrosis on biopsy, but no significant chronic liver disease. Nerve conduction studies confirmed an axonal sensory motor polyneuropathy, and sural nerve biopsy showed a severe chronic axonal neuropathy with only occasional surviving myelinated axons. Detailed analysis of skeletal muscle biopsy showed rare ragged-red fibers, decreased COX reactivity, focal subsarcolemmal accumulation of abnormal mitochondria, and mtDNA deletions, all of which suggested a disorder of mtDNA maintenance. Laboratory studies showed increased CSF lactate and protein levels. The patient's sister developed a progressive, fatal hepatitis at age 9 years, and his father had an episode of hepatitis as a child, but recovered. Additional family details were not available.

Choi et al. (2015) reported 2 unrelated Korean patients with onset of a progressive sensorimotor peripheral neuropathy at 9 and 13 years of age. Both had normal early motor development and presented with distal muscle weakness and atrophy of the lower limbs resulting in difficulty walking and the need for leg braces. The distal upper limbs were similarly, but less severely, affected. Physical examination showed atrophy of the intrinsic hand, foot, and calf muscles, as well as flexion deformities of the interphalangeal joints, ankle contractures, and scoliosis. Other features included decreased vibration and position sense and hyporeflexia of the lower limbs. Nerve conduction velocities were consistent with an axonal sensorimotor neuropathy. Sural nerve biopsy in 1 patient showed loss of large and medium myelinated fibers without evidence of demyelination or onion bulb formation. Muscle biopsy from the other patient showed a few ragged red fibers and myofibers with focal subsarcolemmal accumulation of abnormal mitochondria. MRI of the lower limbs in both patients showed fatty replacement of the soleus muscles, consistent with length-dependent axonal degeneration. Both had mildly increased serum lactate. Neither patient had cerebellar or pyramidal signs, cognitive impairment, or liver dysfunction at ages 34 and 22 years.

Baumann et al. (2019) reported 5 patients from 2 unrelated families with CMT2EE. Family 1 was of Bosnian origin and family 2 from Iraq. The patients presented between 8 and 23 years with distal muscle weakness and instability of the lower limbs. The disorder was progressive, and patients had severe distal muscle atrophy, ankle joint instability, and sometimes foot deformities, such as pes cavus or claw toes. The upper limbs became affected later, resulting in atrophy of the intrinsic hand muscles, decreased muscle strength in the hands, and sometimes claw hand deformities. All patients had significant walking difficulties by age 20; 2 became wheelchair-bound at ages 39 and 27, whereas the other patients used orthotics or a cane. The patients also had distal sensory impairment, particularly in the lower limbs, although none developed acral ulcerations. One patient showed restrictive lung dysfunction at age 43. None of the patients had liver involvement or evidence of liver dysfunction on laboratory studies. Nerve conduction studies showed progressive and variably decreased or absent sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP) of the lower and upper limbs. Motor nerve conduction velocities were normal, consistent with an axonal neuropathy.

The transmission pattern of CMT2EE in the families reported by Choi et al. (2015) and Baumann et al. (2019) was consistent with autosomal recessive inheritance.

In a 21-year-old Pakistani man with CMT2EE, Blakely et al. (2012) identified a homozygous missense mutation in the MPV17 gene (P98L; 137960.0008). The mutation was found by direct sequencing of MPV17 and 2 other genes implicated in mitochondrial DNA maintenance disorders with hepatocerebral involvement; DNA from family members was not available for analysis. Functional studies of the variant were not performed.

In 2 unrelated Korean patients with CMT2EE, Choi et al. (2015) identified a homozygous missense mutation in the MPV17 gene (R41Q; 137960.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Transfection of the R41Q mutation into murine motor neurons inhibited cell proliferation, caused reduced of several OXPHOS proteins, and induced mtDNA depletion compared to controls.

Baumann et al. (2019) identified a homozygous R41Q mutation in the MPV17 gene in 2 Bosnian patients with CMT2EE. The mutation was found by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Three Iraqi brothers from the religious minority of 'Jesidians' (Yazidis) in northern Iraq with the disorder were found to have a homozygous splice site mutation in the MPV17 gene (137960.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The findings expanded the phenotype associated with biallelic MPV17 mutations.