A number sign (#) is used with this entry because of evidence that autosomal recessive peripheral neuropathy with or without impaired intellectual development (PNRIID) is caused by homozygous or compound heterozygous mutation in the MCM3AP gene (603294) on chromosome 21q22.

Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017).

Schuurs-Hoeijmakers et al. (2013) reported a Dutch brother and sister, born of unrelated parents, with mildly impaired intellectual development, progressive polyneuropathy, cerebellar ataxia, ptosis, saccadic eye movements, hypotonia, and facial dysmorphism. The family was ascertained from a cohort of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing.

Ylikallio et al. (2017) reported 9 patients from 5 unrelated families of various ethnic origins with a complex neurologic disorder beginning in infancy or early childhood. The patients ranged in age from 3 to 28 years. Initial features included hypotonia and mildly delayed motor development with most patients achieving walking by age 2 years, although 2 unrelated patients achieved walking at age 4 years. Almost all patients lost independent ambulation between 10 and 24 years and became wheelchair-bound. All patients had evidence of a sensorimotor peripheral neuropathy, and most had distal muscle atrophy and weakness and impaired distal sensation associated with decreased or absent lower limb reflexes. Electrophysiologic studies were consistent with an axonal neuropathy in most patients, but 2 brothers, born of consanguineous Turkish parents (family T), had nerve conduction studies (NCV) suggestive of a demyelinating neuropathy. Sural nerve biopsies, performed in some patients, showed loss of myelinated axons. Seven of 9 patients had mild to moderate intellectual disability with learning difficulties and often with delayed speech, but several could read and attend special schools. Brain imaging, performed in 7 patients, was normal in 4, but showed mildly increased signal intensities in the temporal lobe in 2 patients and mild ventriculomegaly and small white matter cysts in a third. Two sisters in 1 family (family C) had obesity and primary ovarian failure. Additional uncommon features, seen only in a single patient or a few patients, included extensor plantar responses, short stature, microtia with hearing impairment, strabismus, amblyopia, hypotonia, seizures, scoliosis, and distal contractures. One patient was ventilator-dependent at age 14.

Karakaya et al. (2017) reported 4 patients from 3 unrelated families with early-onset autosomal recessive peripheral neuropathy. An 8-year-old girl, born of consanguineous Kurdish parents (family A), had delayed motor development, gait difficulties, ophthalmoplegia, and strabismus. She was able to walk at age 4 years. Physical examination showed distal muscle atrophy and weakness of the upper and lower limbs, absent reflexes, and scoliosis. Nerve conduction studies were consistent with an axonal sensorimotor neuropathy. In a second family, 2 adult sisters, born of consanguineous Iranian parents (family B), developed distal muscle atrophy and weakness in the upper and lower limbs at age 10 to 13 years. They had thenar atrophy, mild wasting of the intrinsic hand muscles, and distal spinal muscular atrophy resulting in hand weakness, writing difficulty, and claw hands. Both also had pes cavus with Achilles tendon shortness, difficulty walking with frequent falls and abnormal gait, and loss of the ability to run. Electrophysiologic studies showed low motor NCVs with normal sensory NCVs. Hearing, vision, and cognition were normal. The last patient was a 13-year-old girl who showed global developmental delay from infancy and later developed progressive distal motor impairment in childhood with difficulty walking. She had mild intellectual disability. Other features included arched feet and kyphosis. NCV was consistent with an axonal sensorimotor neuropathy, and sural nerve biopsy showed mild chronic axonal neuropathy with mild loss of large diameter axons.

Kennerson et al. (2018) reported 3 sibs, born of consanguineous Lebanese parents, with early-onset autosomal recessive peripheral neuropathy. The patients were young adults at the time of the report, but developed slowly progressive distal muscle weakness of the upper and lower limbs between ages 6 and 10 years after early normal motor development. In the teenage years, all had foot drop, wrist and finger drop, marked distal muscle atrophy, and decreased sensation to pain and temperature; vibration and proprioception were normal. The patients remained ambulatory. Electrophysiologic studies showed absent or markedly reduced compound motor action potentials and decreased motor conduction velocities, although sensory studies were basically normal. All 3 patients became obese, and 2 developed type 2 diabetes mellitus. One sib developed psychosis with catatonia, but cognition level was not reported.

Woldegebriel et al. (2020) reported 3 patients, including a sib pair, with PNRIID. One patient (NL2), aged 4 years and 9 months, had developmental delay noted at 3 months of age. At 16 months of age, she had motor delay, hypotonia, swallowing abnormalities, and dyskinetic movements. She had severe scoliosis and slow motor progression at 2 years of age. At 4 years and 8 months of age, after experiencing viral illnesses, she had developmental regression and developed a requirement for ventilatory support. A brain MRI at 10 months of age was normal and a brain MRI at 4 years and 9 months showed hyperintensity of the basal ganglia and mild ventriculomegaly. EMG demonstrated severe polyneuropathy. The Estonian sibs (EST1 and EST2), who were in their twenties, had developmental delay in the first year of life. Severe generalized epilepsy and mild spastic diplegia were diagnosed in patient EST1 at 3.5 years of age and in patient EST2 at 8 years of age. The sibs developed developmental regression, polyneuropathy, and drug resistant epilepsy at 11 years of age in patient EST2 and 12 years of age in patient EST1. They both had progressive muscle atrophy, spasticity, ataxia, dysarthria, and behavioral concerns. At 27 and 28 years of age, they had moderate to severe intellectual disability and epilepsy, and they could not walk.

The transmission pattern of PNRIID in the families reported by Ylikallio et al. (2017) was consistent with autosomal recessive inheritance.

In a Dutch brother and sister, born of unrelated parents, with mild intellectual disability, Schuurs-Hoeijmakers et al. (2013) identified a homozygous missense mutation in the MCM3AP gene (E915K; 603294.0001) affecting a highly conserved residue in the Sac3 domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. DNA from the parents was not available for segregation analysis. Schuurs-Hoeijmakers et al. (2013) noted that the MCM3AP gene is expressed in the brain or in neuronal tissue.

In 9 patients from 5 unrelated families with PNRIID, Ylikallio et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0002-603294.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients in 4 families were compound heterozygous for a missense mutation affecting a conserved residue and a frameshift, nonsense, or splice site mutation, predicted to result in a loss of function or to be subjected to nonsense-mediated mRNA decay. Fibroblasts derived from 1 patient (family F) showed significantly decreased levels of MCM3AP mRNA and protein levels of 20% compared to controls, whereas fibroblasts from the affected individual in family A showed a milder decrease in protein levels at about 85% of controls. Patient cells did not show a deficit in DNA repair. Ylikallio et al. (2017) postulated that the mutations resulted in a partial or complete loss of protein function, possibly leading to abnormal nuclear retention of mRNAs that are crucial for neuronal function.

In 4 patients from 3 unrelated families with PNRIID, Karakaya et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0006 and 603294.0007). The mutations were found by targeted sequencing of a gene panel and confirmed by Sanger sequencing. Segregation studies confirmed recessive inheritance in 2 of the families. Functional studies of the variants and studies of patient cells were not performed, but 2 families carried homozygous missense mutations in the Sac 3 domain, and the third family was compound heterozygous for a nonsense and a frameshift mutation. Two families were consanguineous and of Kurdish and Iranian descent, respectively.

In 3 sibs of Lebanese ethnicity with PNRIID, Kennerson et al. (2018) identified a homozygous missense mutation in the Sac3 domain of the MCM3AP gene (L870S; 603294.0008). 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 of Dutch and Thai ancestry and 2 Estonian sibs with PNRIID, Woldegebriel et al. (2020) identified compound heterozygous mutations in the MCM3AP gene (603294.0009-603294.0012). All 4 mutations were located outside of the Sac3 domain of the GANP protein. MCM3AP mRNA expression was reduced in patient fibroblasts compared to controls, and protein levels were reduced at the level of the nuclear envelope in patient fibroblasts compared to controls.