Hereditary Mitochondrial Myopathy with Lactic Acidemia, A DeToni-Fanconi-Debr?? Syndrome, and a Defective Respiratory Chain in Voluntary Striated Muscles

Abstract

A patient suffering froma mitochondrial myopathy leading to severe insufficiency of the voluntary muscles is described. Severe cerebral damage was present. Major biochemical symptoms were extreme lactic acidemia, hypophosphatemia and hyperphosphaturia, and generalized aminoaciduria, renal glucosuria, and polyuria. Muscular insufficiency resulted in lethal asphyxiz. All therapeutic trials were insufficient. The patient and two other children of the same family with a similar clinical picture all died before the 4th month of life. The condition is probably inherited in an autosomal recessive way. A defective respiratory chain in the mitochondria of the striated muscles is proposed as the underlying mechanism. Cytochromes aa3 were absent, b was nearly absent, but cc1 was present. In heart muscle cytochromes aa3 and b were at the level of the controls.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…Interestingly, mutations to these three subunits are rare. First identified in 1977 [86], CIV deficiencies (OMIM # 220110) can present as myopathies, facial dimorphism and lactic acidosis [86,87]. The majority of known pathogenic mutations are in nDNA genes that encode CIV structural subunits or assembly factors [60], including COX6B1 [88], and PET100 [89] (Table 1).…”

Lactic Acidosis and Mitochondrial Myopathy Associated with Deficiency of Several Components of Complex III of the Respiratory Chain

“…In several of the mitochondrial deficiencies, tissues other than skeletal muscle may be involved. Examples are the cardiomyopathy associated with muscle carnitine deficiency (21), or the renal Fanconi syndrome described in several patients with cytochrome c oxidase deficiency (14,43,47). Involvement of the CNS also occurs in many of these conditions and may cause overwhelming clinical disease.…”

“…Patients with less severe defects of this system have a much milder phenotype with intermittent ataxia and minimal lactic acidosis (23). Severe lactic acidosis is frequent in patients with pyruvate carboxylase deficiency (2,22,39,48) and mild to severe lactic acidosis is found in defects of the respiratory chain (14,25,26,(31)(32)(33)40,43,47,49).…”

Neonatal De Toni-Debré-Fanconi syndrome due to a defect in complex III of the respiratory chain

“…1). It is relatively common in fatal infantile myopathy due to cytochrome c oxidase (complex IV) de ficiency [2,9,15] and has also been reported as a feature o f complex I and combined complex III/IV deficiencies [6,7,11]. Moreover, De Toni-Debré-Fanconi syndrome is invariably involved at a late stage of Pearson syndrome, a mitochondrial disorder with a mitochondrial DNA dele tion affecting different organs including the kidneys [4,8,10,13].…”