Fatal Neonatal-Onset Mitochondrial Respiratory Chain Disease with T Cell Immunodeficiency

Abstract

ABSTRACT:We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporooccipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes IIϩIII and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8 ϩ T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8 ϩ T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease. with clinical manifestations, which may be caused by mutations of nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Due to diverse genetic causes and occurrence in various developmental stages, tissues, or systems, there is a wide variability in clinical phenotype that spans all age groups (1). As many of the RC disorders involve brain and skeletal muscle, these disorders are also known as mitochondrial encephalomyopathies (2). Nevertheless, given the essential role of oxidative phosphorylation in tissue function, virtually all tissues and organs can be involved, accounting for a diverse array of multisystem disorders with a large variety of clinical symptoms in both childhood and adulthood.MDS is defined as a reduction of mtDNA copy number compared with nDNA in different tissues, which leads to insufficient synthesis of RC complexes I, III, IV, and V (3). Autosomal recessive mutations of five nuclear genes have been identified in MDS patients with different clinical presentations (2,4 -7). The onset of symptoms usually occurs during the first year of life and most patients die in early childhood. Thymidine phosphorylase (ECGF1) defects are associated with leukodystrophy and gastrointestinal disorders (8). Mutations in deoxyguanosine kinase (DGUOK) (9) and polymerase gamma (POLG1) (10,11) were described in the hepatocerebral form of MDS, whereas thymidine kinase 2 (TK2) mutations are associated with a mostly myopathic phenotype and CK elevation (12). Most recently, mutations in the succinyl-CoA synthase (SUCLA2) were identified in four infants of a single family reported with severe psychomotor retardation, epilepsy, hearing loss, Leigh-like les...

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