This review highlights recent contributions regarding clinical heterogeneity, pathogenic mechanisms, therapeutic trials, and animal models of the muscle glycogenoses.
Most recent publications have ...dealt with the clinical effects of enzyme replacement therapy (ERT) in glycogenosis type II (Pompe disease), including the cognitive development of children with the infantile form who have reached school age. Standardized exercise testing has shown the similarity between McArdle disease and one of the most recently described muscle glycogenoses, phosphoglucomutase deficiency. Cycle ergometry in patients with glycogenosis type III (debrancher deficiency) without overt weakness has documented exercise intolerance relieved by glucose infusion, consistent with the glycogenolytic block. A mouse model of McArdle disease faithfully recapitulates most features of the human disease and will prove valuable for a better understanding of pathogenesis and therapeutic modalities. Polyglucosan body myopathy with cardiomyopathy has been associated with mutations in RBCK1, a ubiquitin ligase, which have also been reported in children with early-onset immune disorder. The role of polyglucosan storage in muscle and in both central and peripheral nervous systems has been confirmed in the infantile and late-onset forms of glycogenosis type IV (brancher enzyme deficiency). Additional novel findings include the involvement of the heart in one patient with phosphofructokinase (PFK) deficiency and the presence of tubular aggregates in a manifesting heterozygote with phosphoglycerate mutase deficiency.
Important recent developments in the field of muscle glycogenoses include a new disease entity, a new animal model of McArdle disease, and better knowledge of the pathogenesis in some glycogenoses and of the long-term effects of enzyme replacement therapy in Pompe disease.
To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information ...and for clinical trial planning.
We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives).
Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives.
Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.
Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a ...rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10, while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high‐resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow‐up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult‐onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.
Summary Two major groups of inborn errors of energy metabolism are reviewed –glycogenoses and defects of the mitochondrial respiratory chain – to see how often these disorders present in fetal life ...or neonatally. After some general considerations on energy metabolism in the pre- and postnatal development of the human infant, different glycogen storage diseases and mitochondrial encephalomyopathies are surveyed. General conclusions are that: (i) disorders of glycogen metabolism are more likely to cause ‘fetal disease’ than defects of the respiratory chain; (ii) mitochondrial encephalomyopathies, especially those due to defects of the nuclear genome, are frequent causes of neonatal or infantile diseases, typically Leigh syndrome, but usually do not cause fetal distress; (iii) notable exceptions include mutations in the complex III assembly gene BCS1L resulting in the GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death), and defects of mitochondrial protein synthesis, which are the ‘new frontier’ in mitochondrial translational research.
To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
High levels of ventricular lactate, the ...brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.
The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.
During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.
DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
Human CoQ10 deficiencies Quinzii, C. M.; López, L. C.; Naini, A. ...
BioFactors (Oxford),
2008, 2008-00-00, 20080101, Letnik:
32, Številka:
1-4
Journal Article
Recenzirano
Odprti dostop
Coenzyme Q10 (CoQ10 or ubiquinone) is a lipid‐soluble component of virtually all cell membranes and has multiple metabolic functions. A major function of CoQ10 is to transport electrons from ...complexes I and II to complex III in the respiratory chain which resides in the mitochondrial inner membrane. Deficiencies of CoQ10 (MIM 607426) have been associated with four major clinical phenotypes: 1) encephalomyopathy characterized by a triad of recurrent myoglobinuria, brain involvement, and ragged‐red fibers; 2) infantile multisystemic disease typically with prominent nephropathy and encephalopathy; 3) cerebellar ataxia with marked cerebellar atrophy; and 4) pure myopathy. Primary CoQ10 deficiencies due to mutations in ubiquinone biosynthetic genes (COQ2, PDSS1, PDSS2, and ADCK3 CABC1) have been identified in patients with the infantile multisystemic and cerebellar ataxic phenotypes. In contrast, secondary CoQ10 deficiencies, due to mutations in genes not directly related to ubiquinone biosynthesis (APTX, ETFDH, and BRAF), have been identified in patients with cerebellar ataxia, pure myopathy, and cardiofaciocutaneous syndrome. In many patients with CoQ10 deficiencies, the causative molecular genetic defects remain unknown; therefore, it is likely that mutations in additional genes will be identified as causes of CoQ10 deficiencies.
Coenzyme Q10 (CoQ10) deficiency has been associated with various clinical phenotypes, including an infantile multisystem disorder. The authors report a 33-month-old boy who presented with ...corticosteroid-resistant nephrotic syndrome in whom progressive encephalomyopathy later developed. CoQ10 was decreased both in muscle and in fibroblasts. Oral CoQ10 improved the neurologic picture but not the renal dysfunction.
Primary muscle coenzyme Q10 (CoQ10) deficiency is an apparently autosomal recessive condition with heterogeneous clinical presentations. Patients with these disorders improve with CoQ10 ...supplementation. In a family with ataxia and CoQ10 deficiency, analysis of genome-wide microsatellite markers suggested linkage of the disease to chromosome 9p13 and led to identification of an aprataxin gene (APTX) mutation that causes ataxia oculomotor apraxia (AOA1 MIM606350). The authors' observations indicate that CoQ10 deficiency may contribute to the pathogenesis of AOA1.
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