A number sign (#) is used with this entry because of evidence that peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is caused by compound heterozygous mutation in the TRMT5 gene (611023) on chromosome 14q23.

Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022).

For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Powell et al. (2015) reported 2 unrelated patients with a highly variable phenotype resulting from a defect in mitochondrial respiratory chain activity. One of the patients (patient 73901), previously reported by Haller et al. (1989), was a woman who presented at age 25 years with a life-long history of exercise intolerance with prominent exertional dyspnea. Evaluation showed lactic acidosis and a mitochondrial myopathy associated with a deficiency of complexes III and IV. Over the following years, she developed exocrine insufficiency with malabsorption, glucose intolerance, renal tubulopathy, cirrhosis, spasticity with hyperreflexia and extensor plantar responses, and mild distal paresthesia consistent with a peripheral neuropathy. The weakness was progressive. A repeat muscle biopsy showed decreased activity of mitochondrial complexes I, III, and IV, whereas values in fibroblasts were normal. Cognitive and cardiac function were normal. She died in her sleep at age 55 years. The second patient (patient 65205) was a 7-year-old boy with early-onset growth retardation, hypotonia, poor feeding, delayed psychomotor development, and hypertrophic nonobstructive cardiomyopathy. He had mild dysmorphic signs, including triangular face with small mouth, blue sclerae, and maxillary fused primary incisor. Brain imaging showed mild brain atrophy and delayed myelination. Serum lactate was increased on several occasions. Muscle biopsy showed myopathic features without ragged-red fibers, decreased activity of mitochondrial complex IV, and borderline low complex I activity; these activities in fibroblasts were normal. Additional features included delayed nerve conduction and gastrointestinal dysmotility. At age 7 years, he had hypotonia with hyporeflexia, was unable to sit, stand, or walk unsupported, and had limited speech.

Tarnopolsky et al. (2017) reported 2 sisters, 46 and 51 years of age, with variable neuromuscular abnormalities beginning in childhood. The younger sister presented at 27 years with a lifelong history of exercise intolerance and muscle weakness. EMG was normal at first, but later electrophysiologic studies showed a progressive axonal sensory neuropathy. At age 46, she had a waddling and spastic gait with brisk knee reflexes and extensor plantar responses. Mitochondrial respiratory chain analysis showed decreases in complex I, III, and IV activity and reduced maximal oxygen capacity. Her sister had a more severe disease course. She was born prematurely at 32 weeks' gestation and showed global developmental delay, frequent falls associated with cerebral palsy, and learning difficulties in school. She had mild proximal and severe distal muscle weakness and atrophy of the lower limbs associated with spasticity and extensor plantar responses. She also had progressive visual loss due to optic atrophy. After a surgical procedure at age 42, she developed seizures associated with a stroke-like episode, which the authors noted was reminiscent of MELAS (see 540000). She became depressed, catatonic, developed dementia, and was wheelchair-bound. Muscle biopsy in the younger sister showed marked COX deficiency and subsarcolemmal mitochondrial aggregates, whereas muscle biopsy in the older sister showed internalized nuclei with intranuclear inclusions, variation in fiber size, and no COX-negative fibers. Both patients showed intermittently increased lactate levels. Tarnopolsky et al. (2017) emphasized the phenotypic variability even within the same family.

Argente-Escrig et al. (2022) reported 3 unrelated patients, aged 17, 15, and 9 years, with PNSED. The patients presented in infancy or early childhood with global developmental delay, delayed or absent walking, and frequent falls associated with a predominantly sensory demyelinating peripheral neuropathy mainly affecting the lower limbs. They had foot deformities, including pes cavus, pes planus, and hammertoes, as well as Achilles tendon contractures. All required ankle-foot orthoses, but they eventually became wheelchair-bound between 6 and 14 years of age. Additional features included hypotonia, hyporeflexia, tiptoe walking, and foot drop, but also extensor plantar responses and upgoing toes. Upper limb involvement was manifest by intrinsic hand muscle weakness, sometimes with atrophy and claw hands, poor fine motor skills, and distal sensory impairment. All 3 patients had moderate to severely impaired intellectual development, some with behavioral problems such as ADHD and inattention, but they were able to attend schooling with special needs assistance. P2 was a 15-year-old boy who experienced several complex partial seizures during childhood between 14 months and 7 years of age; this patient had bulbar dysfunction, generalized contractures, poor sphincter control, and severe speech difficulties. Other common features included short stature, scoliosis or hyperlordosis, and cerebellar signs, such as ataxia, saccadic eye movements, and dysmetria and dysdiadochokinesis in the upper limbs. Brain imaging showed variable degrees of cerebellar atrophy and nonspecific hyperintense foci in the subcortical white matter. Distal skeletal muscle biopsies showed signs of chronic denervation with some enlarged mitochondria, but enzymatic analysis of the respiratory chain showed mild complex I deficiency only, in 1 patient. The patients did not exhibit exercise intolerance. Peripheral nerve biopsy showed loss of myelinated fibers and irregular myelin shapes.

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

In 2 unrelated patients with variable manifestations of NMSED, Powell et al. (2015) identified compound heterozygous mutations in the TRMT5 gene (611023.0001-611023.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated within the families according to DNA available from family members. A reverse-transcription primer extension (RT-PEx) assay performed on patient-derived fibroblasts and skeletal muscle tissue indicated that mt-tRNA(Leu-CUN) had decreased G37 modification compared to controls, with a more significant effect on the patient with the more severe phenotype. In addition, neither missense mutation was able to rescue defective mitochondrial respiratory activity in a yeast knockout model, consistent with a loss of function. The findings indicated that TRMT5 is responsible for G37 modification in human mitochondrial tRNA molecules.

In 2 sisters with NMSED, Tarnopolsky et al. (2017) identified compound heterozygous mutations in the TRMT5 gene (611023.0001 and 611023.0002). The mutations were found by whole-exome sequencing. Functional studies were not performed.

In 3 unrelated patients with NMSED, Argente-Escrig et al. (2022) identified compound heterozygous mutations in the TRMT5 gene (611023.0001 and 611023.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.