Recurrent Sensory-Motor Neuropathy Mimicking CIDP as Predominant Presentation of PDH Deficiency

Abstract

Introduction: PDH deficiency (OMIM # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders. Isolated peripheral neuropathy as predominant clinical presentation is uncommon. Results: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated CSF proteins, suggested a chronic inflammatory polyneuropathy (CIDP). The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in 5 patients with a similar phenotype. A 3D-reconstruction demonstrated that mutations affecting this Arg88 destabilize the interactions between the subunits of the E1 complex. Conclusion: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis. In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

“…The mutation is deleterious (CADD PHRED score 24.4; Revel score 0.82) and involved a residue highly conserved through evolution from human to zebrafish localized in the conserved tubulin C-terminal protein domain (IPR023123). Using freely available tools to assess the impact of missense variants in protein stability and assembly [ 17 ], we showed that the p.Glu415Lys variant had a likely destabilizing effect (ΔΔG − 0.61) on α-tubulin stability (Fig. 1 B).…”