ORPHA: 3208;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.13 | Mitochondrial complex II deficiency, nuclear type 4 | 619224 | Autosomal recessive | 3 | SDHB | 185470 |
A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency nuclear type 4 (MC2DN4) is caused by homozygous or compound heterozygous mutation in the succinate dehydrogenase complex subunit B gene (SDHB; 185470) on chromosome 1p36.
Mitochondrial complex II deficiency nuclear type 4 (MC2DN4) is a severe autosomal recessive disorder characterized by early-onset progressive neurodegeneration with leukoencephalopathy. Acute episodes of neurodegeneration are often triggered by catabolic stress such as infection or fasting.
Alston et al. (2012) reported an Asian girl, born of consanguineous parents, with neurologic impairment, leukoencephalopathy, and biochemical evidence of mitochondrial complex II deficiency. The patient showed developmental regression beginning at age 1 year. She was hypotonic with joint contractures, and she became wheelchair-bound at age 4 years. Brain MRI showed leukodystrophy in the deep white matter and signal abnormalities in the corpus callosum. MR spectroscopy showed increased lactate and increased succinate in the dystrophic white matter.
Ardissone et al. (2015) reported a Pakistani girl who presented at 15 months of age with acute psychomotor depression that developed several days after a febrile illness. On evaluation one month later, she had general hypotonia, hyperreflexia, lack of postural control, and irritability. Laboratory studies showed elevated plasma lactate and pyruvate and elevated 2-ketoglutarate in the urine. Brain MRI showed diffuse hyperintensity of the hemispheric white matter and corpus callosum with sparing of the subcortical U-fibers, hyperintensities of the bilateral thalami, and cystic degeneration of the deep white matter. HNMR-spectroscopy revealed succinate and lactate peaks. Visual evoked potential testing showed central conduction abnormalities. Her healthy 11-year-old sib had the same homozygous mutation in the SDHB gene (D48V; 185470.0020), leading Ardissone et al. (2015) to hypothesize that triggering stimuli may have been necessary to produce a clinical phenotype.
Vanderver et al. (2016) reported a Turkish boy (patient LD_0756.0A), born of consanguineous parents, who had motor delays from birth and acutely decompensated at 7 months of age. He had ataxia, hypotonia, and spasticity. Brain MRI at 3.5 years of age showed abnormal signal in the supratentorial white matter with sparing of the U-fibers, a swollen appearance of the corpus callosum, and involvement of the cerebellar white matter of the brainstem.
Helman et al. (2016) reported clinical and radiologic features in 5 patients, 4 of whom were living (patients 10, 11, 16 and 19) with an age range of 19 months to 9 years, and one of whom died at 1 year of age from respiratory failure (patient 15). Age of onset of symptoms ranged from birth to 18 months. In the 4 patients who had an MRI within the first 2 years of life, all had involvement of the corpus callosum and the thalamic nuclei, 3 had involvement of the middle cerebellar peduncles and pons, 3 had involvement of the spinal cord, 3 had involvement of the corticospinal tracts, and 2 had involvement of the cerebellar white matter. Patient 10 had spastic tetraparesis and normal cognition. Patient 11 had dilated cardiomyopathy with significant hypertrophy and poor function, gross motor impairment with contractures, and intact cognition. Patient 16 had spastic diplegia with severe motor difficulties and severe cognitive impairment. Patient 19 had generalized hypotonia, lack of postural control, irritability, and moderate cognitive impairment.
Gronborg et al. (2017) reported 2 unrelated patients with complex II deficiency. Patient 1, a Lebanese girl born to consanguineous parents, had slight developmental delay and hypotonia in the first year of life. She then had a progressive loss of developmental milestones starting at age 12 months, which was more pronounced during infections. At age 15 months, she had truncal hypotonia and increased muscle tone and increased reflexes in the limbs. She had slight bilateral optic atrophy, reduced vision, and horizontal nystagmus with opsoclonus. Brain MRI at age 16 months showed signal intensities in the frontal, parietooccipital, and posterior temporal white matter with sparing of the juxtacortical fibers. Laboratory studies showed an increased blood lactate and increased ketones and Krebs cycle intermediates (especially succinate) in the urine. She died at age 25 months of multiorgan failure in the setting of a respiratory infection. Patient 2, a boy born of nonconsanguineous parents, had intrauterine growth retardation, with decreased head circumference, length, and weight at birth. Starting at age 6 months, he had progressive loss of acquired skills, which was worse during infections. At age 9 months, he had pneumonia and respiratory failure necessitating assisted ventilation, and he had further loss of developmental skills. Laboratory studies showed increased blood lactate, increased ALAT and ASAT, increased creatine kinase, and increased INR. He had cardiomyopathy with severe dilatation and hypertrophy of the septum and posterior wall of the left ventricle. MRI at age 11 months showed signal intensities in the frontal, parietooccipital, and posterior temporal white matter with sparing of the juxtacortical fibers. He was stable with some improvement until 1 year of age when he died from multiorgan failure and cardiac arrest.
Kaur et al. (2020) reported an Indian boy who had regression of milestones at 1 year of age. He developed febrile seizures at age 18 months. On examination, he had increased tone in all limbs and brisk deep tendon reflexes. Ophthalmologic examination revealed bilateral optic atrophy. Brain MRI showed confluent lesions in the periventricular white matter, corpus callosum, dorsomedial thalami, brainstem, and spinal cord. Plasma and CSF lactate were elevated.
The transmission pattern of MC2DN4 in the patients reported by Alston et al. (2012) and Ardissone et al. (2015) was consistent with autosomal recessive inheritance.
In an Asian girl, born of consanguineous parents, with neurologic impairment, leukoencephalopathy, and biochemical evidence of mitochondrial complex II deficiency, Alston et al. (2012) identified a homozygous missense mutation in the SDHB gene (D48V; 185470.0020). Her unaffected parents were heterozygous for the mutation. Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples.
In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the previously reported D48V mutation in the SDHB gene. The mutation was found by sequencing of a panel of 7 genes associated with complex II deficiency. A clinically unaffected sib was also homozygous for the mutation. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib. SDHA protein was also reduced in these cells, possibly due to instability of complex II assembly.
In a Turkish boy, born of consanguineous parents, with MC2DN4, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene.
In 6 patients with MC2DN4, Helman et al. (2016) identified mutations in the SDHB gene. Five patients had the D48V mutation, 4 (patients 10, 11, 16, and 19) in homozygous state and 1 (patient 15) in compound heterozygous state.
In 2 unrelated children with MC2DN4, Gronborg et al. (2017) identified mutations in the SDHB gene: a Lebanese girl, born of consanguineous parents, was homozygous for a missense mutation (L257V; 185470.0022), and a boy, born of nonconsanguineous parents, was compound heterozygous for D48V and another missense mutation (R230H; 185470.0023). In both patients, SDHB protein content was reduced in patient fibroblasts, muscle fibers showed diffuse and severe lack of SDH staining, and complex II enzyme activity was severely deficient in muscle. The parents of both children were confirmed to be mutation carriers. Gronborg et al. (2017) noted that the R230H mutation was previously reported in heterozygous state in patients with paraganglioma by several authors, including Cerecer-Gil et al. (2010).
In a male infant with MC2DN4, who was born to nonconsanguineous Indian parents, Kaur et al. (2020) identified a homozygous missense mutation in the SDHB gene (A102T; 185470.0024). The parents were heterozygous for the mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.
Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J. Med. Genet. 49: 569-577, 2012. [PubMed: 22972948] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101146]
Ardissone, A., Invernizzi, F., Nasca, A., Moroni, I., Farina, L., Ghezzi, D. Mitochondrial leukoencephalopathy and complex II deficiency associated with a recessive SDHB mutation with reduced penetrance. Molec. Genet. Metab. Rep. 5: 51-54, 2015. [PubMed: 26925370] [Full Text: https://doi.org/10.1016/j.ymgmr.2015.10.006]
Cerecer-Gil, N. Y., Figuera, L. E., Llamas, F. J., Lara, M., Escamilla, J. G., Ramos, R., Estrada, G., Karim Hussain, A., Gaal, J., Korpershoek, E., de Krijger, R. R., Dinjens, W. N. M., Devilee, P., Bayley, J. P. Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma. Clin. Cancer Res. 16: 4148-4158, 2010. [PubMed: 20592014] [Full Text: https://doi.org/10.1158/1078-0432.CCR-10-0637]
Gronborg, S., Darin, N., Miranda, M. J., Damgaard, B., Cayuela, J. A., Oldfors, A., Kollberg, G., Hansen, T. V. O., Ravn, K., Wibrand, F., Ostergaard, E. Leukoencephalopathy due to complex II deficiency and bi-allelic SDHB mutations: further cases and implications for genetic counselling. JIMD Rep. 33: 69-77, 2017. [PubMed: 27604842] [Full Text: https://doi.org/10.1007/8904_2016_582]
Helman, G., Caldovic, L., Whitehead, M. T., Simons, C., Brockmann, K., Edvardson, S., Bai, R., Moroni, I., Taylor, J. M., Van Haren K., SDH Study Group, Taft, R. J., Vanderver, A., van der Knaap, M. S. Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy. Ann. Neurol. 79: 379-386, 2016. Note: Erratum: Ann. Neurol. 84: 481 only, 2018. [PubMed: 26642834] [Full Text: https://doi.org/10.1002/ana.24572]
Kaur, P., Sharma, S., Kadavigere, R., Girisha K. M., Shukla, A. Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: case report and review of the literature. Ann. Hum. Genet. 84: 345-351, 2020. [PubMed: 32124427] [Full Text: https://doi.org/10.1111/ahg.12377]
Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., Khouzam, A., Rajan, V., and 17 others. Whole exome sequencing in patients with white matter abnormalities. Ann. Neurol. 79: 1031-1037, 2016. [PubMed: 27159321] [Full Text: https://doi.org/10.1002/ana.24650]