A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-4 (MMDS4) is caused by homozygous or compound heterozygous mutation in the ISCA2 gene (615317) on chromosome 14q24.

MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by Alaimo et al., 2018).

For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).

Al-Hassnan et al. (2015) reported 5 unrelated consanguineous Arab families in which 6 children had a severe neurologic disorder characterized by onset of neuroregression between ages 3 and 7 months. Two of the families had similarly affected children who were deceased. All 6 patients regressed to a vegetative state with no speech; 4 died before age 5 years. There were no dysmorphic features, but all had spasticity and optic atrophy. Brain imaging showed extensive diffuse bilateral signal abnormalities in multiple brain regions. Skeletal muscle biopsy revealed atrophic and angulated fibers, and patient fibroblasts showed a depletion of mitochondrial DNA copy number and decreased activity of mitochondrial respiratory complex I. No metabolic abnormalities were detected.

Alaimo et al. (2018) reported 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4. The patients had normal development in the first few months of life, but then showed motor regression with hypotonia, spasticity, loss of eye contact, and loss of social interaction. Additional features included optic atrophy with absent visual evoked potentials. One patient had mild skeletal abnormalities, including joint laxity, short fourth metacarpals, and cutaneous toe syndactyly. Laboratory studies in 1 of the patients showed increased CSF glycine, glutamate, and lactate, and decreased 5-methyltetrahydrofolate, although these were all normal in plasma. Metabolic studies in the other patient were not performed. Brain imaging in both patients showed significant leukodystrophy affecting subcortical regions, cerebellum, and brainstem, with extensive involvement of the spinal cord. Both families had a history of several additional patients with fatal infantile leukodystrophy.

Alfadhel et al. (2018) reported 10 children from 9 unrelated consanguineous Saudi families with MMDS4. Many of the families had a history of death of other sibs affected with a similar disorder or of recurrent miscarriages. The patients all had normal early development, but presented between 3 and 7 months of age with loss of developmental milestones, including visual fixation, motor, and language skills, as well as the onset of nystagmus. They had axial hypotonia, poor feeding due to swallowing weakness, peripheral spasticity, and optic atrophy. Three patients had seizures, 2 of whom had single or rare controllable seizures. All patients deteriorated to a vegetative state with a feeding tube. Laboratory studies, when performed, showed inconsistent results: 2 patients had increased CSF glycine and CSF lactate, 3 patients had increased plasma glycine and/or lactate, and several patients had normal plasma levels of glycine and lactate. Brain imaging, performed on most patients, showed white matter abnormalities in the cerebrum, cerebellum, and brainstem, with sparing of the basal ganglia. Five patients died between 11 and 28 months of age, usually due to recurrent chest infections. Alfadhel et al. (2018) noted the phenotypic similarity to LBSL (611105), which is caused by mutation in the DARS2 gene (610956).

Toldo et al. (2018) reported a female infant of Italian descent with MMDS4. She presented at age 2 months with progressive axial hypotonia, motor regression, feeding difficulties, nystagmus, and brisk tendon reflexes. EEG showed generalized slow wave activity. CSF showed increased lactate, and brain imaging showed diffuse T2-weighted hyperintensities in the cortex with extensive involvement of the spinal cord. Analysis of muscle tissue showed reduced activity of mitochondrial complexes II and IV. The patient developed rapidly progressive respiratory failure resulting in death at age 3 months.

The transmission pattern of MMDS4 in the families reported by Al-Hassnan et al. (2015) was consistent with autosomal recessive inheritance.

In 6 children from 5 unrelated consanguineous Arab families with MMDS4, Al-Hassnan et al. (2015) identified a homozygous missense mutation in the ISCA2 gene (G77S; 615317.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the families, and haplotype analysis indicated a founder effect. Patient cells showed decreased expression of ISCA2, ISCA1 (611006), and IBA57 (615316). Functional studies of the ISCA2 variant were not performed, but Al-Hassnan et al. (2015) noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function.

In 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, Alaimo et al. (2018) identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Dermal fibroblasts from 1 of the patients showed diminished mitochondrial membrane potential, variably decreased or increased mitochondrial enzyme complexes, decreased oxygen consumption, and decreased ATP production compared to controls, consistent with mitochondrial dysfunction. There was a decrease in complex II activity and mildly decreased complex IV activity, with intact complexes I and III. The mitochondria also showed morphologic defects as well as decreased mtDNA content, to about 25% of normal values. Patient cells also showed decreased levels of protein lipoylation, indicating a defect in the production of lipoic acid, presumably due to faulty Fe-S cluster generation and specifically affecting the 4Fe-4S-dependent enzyme LIAS (607031). Knockdown of ISCA2 using shRNA resulted in similar cellular abnormalities and defects involving 4Fe-4S-dependent proteins, but not 2Fe-2S proteins.

In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, Alfadhel et al. (2018) identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster.

In an Italian infant with MMDS4, Toldo et al. (2018) identified compound heterozygous mutations in the ISCA2 gene (c.295delT, 615317.0002 and S112G, 615317.0003). The mutations, which were found by next-generation sequencing of a panel of genes associated with mitochondrial disorders, segregated with the disorder in the family. Functional studies of the variant were not performed.