Spinal Cord Calcification in an Early-Onset Progressive Leukoencephalopathy

Abstract

Spinal cord calcifications are an unusual finding in pediatric neurology. We here describe a young child who presented severe psychomotor delay, tetraplegia, deafness, and anemia. Neuroradiological investigations revealed severe leukodystrophy and unusual calcifications in the cerebral white matter and all along the medullary pathways. Common infectious and metabolic diseases were ruled out. A mild reduction in the activity of several respiratory chain complexes was documented on muscle biopsy. Of interest, we found an intronic variant in DARS2, a gene involved in mitochondrial DNA translation, responsible for the syndrome of leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate. In our opinion, our case, and probably 2 previously reported Japanese siblings with a picture very similar to that of our patient, could represent a new, progressive leukoencephalomyelopathy.

Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases

“…Activity of the Respiratory Chain Complexes Sub-units are Differentially Affected Defects in the translation of mt-DNA-encoded RC subunits were reported to be correlated with mutations within YARS2 [97, 111], MARS2 [98], and FARS2 [104]. In addition, defects in the activity of those complexes were reported to be correlated with mutations within YARS2 [97, 111], SARS2 [108], RARS2 [92, 101], MARS2 [98], FARS2 [104], EARS2 [89], DARS2[112], and AARS2[110]. However, affected subunits may vary from one case to another.…”

Calcifying leukoencephalopathies: New overlapping phenotypes

“…We read the article by Kuki et al [2011] on “Progressive Leukoencephalopathy with intracranial calcification, congenital deafness, and developmental deterioration” and we found it very interesting. Recently, we reported a very distinctive patient affected by a calcifying leukoencephalopathy involving spinal cord with a pattern we called “track‐like” calcifications [Orcesi et al, 2011]. Our patient presented with systemic symptoms, notably hypochromic microcytic anemia, a mild proteinuria, and laboratory abnormalities of unclear significance such as increased levels of plasma alanine, low concentration of biopterin in CSF, a mild reduction in the activity of several complexes of the respiratory chain.…”

Haematological abnormalities in mitochondrial disorders

“…PUS1 Riley et al, (10) Sasarman et al (35) X-linked sideroblastic anaemia (XLSA) Anaemia ALAS2 Fontenay et al (12) XLSA with ataxia Anaemia ABCB7 Fontenay et al (12) Leigh-syndrome Anaemia Numerous Nagashima et al (13) LHON Anaemia Several Pott & Wong (15) MELAS Anaemia, thrombocytosis Not reported Finsterer (14) TRMA Megaloblastic anaemia SLC19A2 Fleming, (36) Cazzola & Invernizzi (37) AR-SA Sideroblastic anaemia GLRX5 Fleming, (36) Cazzola & Invernizzi (37) Non-syndromic Anaemia Sideroblastic anaemia SLC25A38 Kannengiesser et al (17) mtDNA depletion Anaemia, thrombopenia, T-cells ↓ POLG1 Reichenbach et al (28) Congenital neutropenia Neutropenia HAX-1 Boztug et al (32) LE, cerebral calcification Anaemia DARS2 Orcesi et al (18) MP, hCMP, SLE Anaemia, thrombopenia CII, IV defect Van Hove et al (25) Haemolytic uremic syndrome Anaemia, thrombopenia CII-defect Micheletti et al (19) Myopathy, lactacidosis Anaemia Not reported Inbal et al (16) AR-SA: autosomal-recessive sideroblastic anaemia; hCMP: hypertrophic cardiomyopathy; LE: leucoencephalopathy; LHON: Leber's hereditary optic neuropathy; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MLASA: autosomal recessive mitochondrial myopathy, lactacidosis and sideroblastic anaemia; MP: myopathy; mtDNA: mitochondrial DNA; SLE: stroke-like episode; TRMA: thiamine-responsive megaloblastic anaemia;…”

“…While anaemia was never the sole phenotypic feature of MID in the present study, it was always present among other phenotypic features of MID (Table VII). (18,22,23) In nonsyndromic MIDs, anaemia has been described as a phenotypic feature in patients with leucoencephalopathy and intracerebral calcifications due to a DARS2 mutation. (18) Anaemia, together with thrombopenia, has been reported in a 40-year-old man with a combined complex II and IV defect, who also presented with myopathy, renal insufficiency, hypertrophic cardiomyopathy, a stroke-like episode and lactacidosis.…”

“…(18,22,23) In nonsyndromic MIDs, anaemia has been described as a phenotypic feature in patients with leucoencephalopathy and intracerebral calcifications due to a DARS2 mutation. (18) Anaemia, together with thrombopenia, has been reported in a 40-year-old man with a combined complex II and IV defect, who also presented with myopathy, renal insufficiency, hypertrophic cardiomyopathy, a stroke-like episode and lactacidosis. (25) Anaemia associated with thrombopenia can also be a feature of haemolytic uraemic syndrome due to a complex II defect.…”