Multiple Mitochondrial Dysfunctions Syndrome 3

A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-3 (MMDS3) is caused by homozygous mutation in the IBA57 gene (615316) on chromosome 1q42.

Description

MMDS3 is an autosomal recessive severe neurodegenerative disorder characterized by loss of previously acquired developmental milestones in the first months or years of life. Some affected patients have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some patients die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some patients may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable. There may be additional biochemical evidence of mitochondrial dysfunction (summary by Liu et al., 2018).

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

Clinical Features

Ajit Bolar et al. (2013) reported 2 sibs, born of consanguineous Moroccan parents, with a lethal encephalomyopathy and myopathy resulting from mitochondrial dysfunction. Prenatal ultrasound of both sibs showed intrauterine growth retardation, polyhydramnios, microcephaly, and dilated cerebral ventricles. At birth, the first child was severely hypotonic with absent primitive reflexes. He had microcephaly and dysmorphic features, including retrognathia, high palate, widely spaced nipples, and arthrogryposis of elbows, wrists, fingers, and knees. Brain MRI showed white matter abnormalities, hypoplasia of the corpus callosum, frontoparietal polymicrogyria, brainstem hypoplasia, and cytotoxic edema of the cortex. Laboratory studies showed severe lactic acidosis and increased glycine in cerebrospinal fluid (CSF). Intensive care was stopped at day 6 of life, and the infant died. The second infant showed similar features and died 15 minutes after birth. Biochemical evaluation of patient tissues showed mitochondrial defects, particularly of respiratory complexes I, II, and IV and the lipoate-containing enzymes alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase. Both the catalytic activities and the amounts of these enzyme complexes were decreased.

Debray et al. (2015) reported a male infant, born of consanguineous Moroccan parents, with MMDS3. He presented at 6 months of age with progressive hypotonia, motor regression, and loss of previously acquired skills, including sitting, babbling, and visual tracking. Other features included feeding difficulties, irritability, opisthotonus, spastic tetraplegia, and respiratory distress, resulting in death at age 17 months. Laboratory studies showed mildly increased serum and CSF lactate and glycine. Brain imaging was consistent with a diffuse leukoencephalopathy, with white matter abnormalities in the cerebral central and periventricular white matter, the cerebellum, and the upper spinal cord. Studies of respiratory chain enzymes in skeletal muscle showed a combined deficiency of the activities of complexes I and II, and decreased protein levels of complexes I, II, and IV. Patient cells also showed a severe decrease in the lipoylation of lipoic acid-dependent enzymes. These findings were consistent with a Fe/S cluster biosynthesis defect.

Torraco et al. (2017) reported 4 unrelated patients with variable severity of MMDS3. The most severely affected patient showed delayed development since birth and presented at 4 months of age with poor feeding, failure to thrive, absence of head control, microcephaly (3rd centile), pendular nystagmus, and impaired visual attention. She later needed a feeding tube and tracheostomy. The other 3 patients presented between 4 and 18 months with acute psychomotor regression after normal early development. Two patients had onset of symptoms soon after receiving a vaccination. The patients had progressive neurologic impairment, with loss of speech, irritability, cognitive impairment, spastic tetraparesis, dystonic posturing, hypotonia, loss of voluntary movements, swallowing impairment, and respiratory failure. Brain imaging showed cerebral and cerebellar white matter abnormalities and/or diffuse cavitating leukoencephalopathy with involvement of the corpus callosum, posterior arm of the internal capsule, posterior fossa structures, brainstem, and spinal cord. EEG in 3 patients showed disorganized background activity, sometimes with epileptiform abnormalities, although only 2 patients were reported to have overt late-onset seizures. Serum lactate and pyruvate were increased in some patients, and brain magnetic resonance spectroscopy showed increased lactate peak. Mitochondrial respiratory chain enzyme and Western blot studies in skeletal muscle or fibroblasts showed variable decreases in complexes I and II, as well as reduced lipoylation of certain proteins, consistent with impairment of the 4Fe-4S cluster-containing enzymes. The most severely affected patient had decreased complex IV activity as well. Two patients died around 2 years of age. One patient was alive at age 16 years, but totally supported by mechanical ventilation and tube feeding. Another patient, who was treated with riboflavin and coenzyme Q10, showed some minor neurologic improvement and had a stable course at age 12 years.

Liu et al. (2018) reported 11 Chinese children, including 2 pairs of sibs, with MMDS3. Seven patients had normal development before disease onset, whereas others had mild delay before disease onset. The median age of symptom onset was 9 months (range 5 to 15). Patients presented with acute/subacute onset of motor regression, agitation, spasticity, and pyramidal signs, and the deterioration peaked within 1 to 4 months. Several patients had infections before the onset of symptoms, and others later had mild deterioration of motor function in response to infection. All patients had survived and were stable at follow-up of 6 months to 10 years. Motor impairment was variable at follow-up: 1 patient was able to walk, whereas others had mild or significant motor impairment. Seven patients who underwent detailed cognitive assessment showed variable deficits ranging from normal communication and problem solving to borderline or delayed in these parameters. Less common features included nystagmus, seizures, and visual impairment. Brain imaging showed cavitating leukoencephalopathy throughout the brain, including the periventricular/central white matter, parietooccipital lobes, corpus callosum, cerebellum, and brainstem. The basal ganglia and thalamus were not involved. There was also evidence of brain atrophy in most patients. Liu et al. (2018) stated that after the initial regression, all cases stabilized and some even improved, although most had residual motor and cognitive deficits. Studies of patient tissue samples were not performed.

Ishiyama et al. (2017) reported 3 patients from 2 Japanese families with MMDS3. The patients had normal early development until the onset of symptoms between 11 months and 2 years of age. They showed marked irritability and episodic loss of skills associated with recurrent infections and increased lactate. These episodes led to psychomotor deterioration, axial hypotonia, and spasticity. Treatment with a mitochondrial cocktail recovered some of the lost skills during periods of remission. Plasma and CSF lactate were intermittently increased. Examination at age 6 to 7 years found variation between normal function and mild cognitive deficits. Brain imaging in all 3 patients showed progressive leukoencephalopathy with extensive signal abnormalities in the periventricular cerebral white matter and corpus callosum. The basal ganglia, cerebellum, and brainstem were spared.

Inheritance

The transmission pattern of MMDS3 in the family reported by Ajit Bolar et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Moroccan parents, with MMDS3, Ajit Bolar et al. (2013) identified a homozygous mutation in the IBA57 gene (Q314P; 615316.0001). The mutation was found by homozygosity mapping and candidate gene sequencing, and was not found in several large control databases or in 186 Moroccan control alleles. In vitro functional expression studies and studies in patient cells showed that the mutant protein had some residual activity, but was subject to proteolytic degradation below physiologically critical levels. The findings indicated that the disorder resulted from defects in mitochondrial Fe/S protein assembly; cytosolic and nuclear Fe/S proteins and iron metabolism were not affected.

In a boy, born of consanguineous Moroccan parents, with MMDS3, Debray et al. (2015) identified a homozygous missense mutation in the IBA57 gene (R146W; 615316.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells and IBA57-null HeLa cells showed depletion of respiratory complexes I and II and decreased levels of lipoic acid-dependent mitochondrial proteins. Complementation studies in IBA57-null HeLa cells showed that the mutant protein was unable to restore the biochemical phenotype, consistent with a loss of function. Patient cells showed a defect in mitochondrial respiratory chains I and II and decreased mitochondrial protein lipoylation, indicating a defect in the biogenesis of Fe/S clusters, particularly 4Fe-4S clusters.

In 4 unrelated patients with MMDS3, Torraco et al. (2017) identified homozygous or compound heterozygous mutations in the IBA57 gene (see, e.g., 615316.0004-615316.0006). The mutations, which were found by targeted sequencing of a panel of genes encoding mitochondrial proteins or by direct sequencing of the IBA57 gene, were confirmed by Sanger sequencing and segregated with the disorder in 3 families from whom parental DNA was available. Western blot analysis of fibroblast mitochondria from patients showed variable decreases in mitochondrial respiratory complexes I, II, and IV, as well as decreased SDHB (185470), and variably decreased lipoylation of mitochondrial dehydrogenases. ISCA2 (615317) was also decreased.

In 11 patients from 9 Chinese families with MMDS3, Liu et al. (2018) identified 8 different biallelic mutations in the IBA57 gene (see, e.g., 615316.0007-615316.0009). There were 5 missense mutations and 3 truncating mutations. Ten of the 11 patients carried the same missense mutation (Y96H; 615316.0007), which was demonstrated to be a founder mutation. Functional studies of the variants and studies of patient cells were not performed.

In 3 patients from 2 families with MMDS3, Ishiyama et al. (2017) identified compound heterozygous mutations in the IBA57 gene (see, e.g., 615316.0010-615316.0011). There was 1 missense mutation and 2 nonsense mutations. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient-derived cells showed a significant decrease in IBA57 protein. Although there was not a significant decrease in mitochondrial enzyme protein levels by Western blot, all patients had decreased activity of complex II. There was also a decrease in SDHB and LIAS (607031), as well as a decrease in the lipoylation of mitochondrial enzymes. NFU1 (608100) was also decreased. These findings were consistent with a deficiency in 4Fe-4S cluster assembly. Expression of wildtype IBA57 restored these biochemical defects, confirming that the mutations resulted in a loss-of-function effect.