The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein

Abstract

Peripheral neuropathy is a known irreversible long-term complication of longchain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), two inherited disorders of mitochondrial long-chain fatty acid oxidation. The underlying pathophysiology of neuropathy is still not fully understood. We report electrophysiological studies and neurological findings in a series of 8 LCHAD-deficient and 11 MTP-deficient patients. The median age at time of the study was 8.0 years (0.5-25 years). The overall prevalence of neuropathy was 58% with neuropathic symptoms being slightly more common in MTPD compared to LCHADD (70% vs 50%, respectively). Onset of neuropathy was significantly earlier in MTPD patients compared to LCHADD patients (median age at onset 4.7 vs 15.3 years, respectively, P = .047). In four patients, isolated peripheral neuropathy was the first and only presenting symptom, and in all four the diagnosis was missed by newborn screening. About half of the patients (45.5%) had a sensorimotor neuropathy, while 27.3% showed a pure motor form and another 27.3% an isolated sensory form. Despite early diagnosis by newborn screening and early initiation of therapy, peripheral neuropathy cannot be prevented in all patients with LCHADD/ MTPD and has severe impact on the life of affected patients. Electrophysiology classifies LCHADD/MTPD neuropathy as axonal with secondary demyelination. A novel observation is that in patients with acute, fulminant onset of neuropathy, symptoms can be partly reversible. Further studies are needed to elucidate the underlying pathophysiology of axonal damage and possible therapeutic targets.

Novel mutations in the HADHB gene causing a mild phenotype of mitochondrial trifunctional protein (MTP) deficiency

“…18 A newly published study on patients with MTP deficiency and neuropathy describes neuropathy as the only presenting symptom in four children. 10 However, variants in the HADHA gene were the likely cause of the metabolic disorder in these cases. On the other hand, in the cases presented in the latter study, the long-lasting episodes of weakness were reversible, mimicking the findings in our three adult patients.…”

“…Recently, Nadjar and colleagues described four MTP cases with a new phenotype with adult‐onset ataxia and sensory ganglionopathy, but these were preceded by rhabdomyolysis in childhood in all cases 18 . A newly published study on patients with MTP deficiency and neuropathy describes neuropathy as the only presenting symptom in four children 10 . However, variants in the HADHA gene were the likely cause of the metabolic disorder in these cases.…”

“…An MTP deficiency subtype with isolated axonal neuropathy resembling Charcot‐Marie‐Tooth type 2 (CMT2) has been described in a few cases from East Asia 9 . A recent study also described neuropathy as the only presenting manifestation in four children with variants in the HADHA gene 10 . In this article, we present three cases with an attenuated phenotype diagnosed in late adolescence/early adulthood without previous episodes of myoglobinuria, rhabdomyolysis, or raised creatine kinase (CK).…”

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

“…Our data suggest that C7 might be more efficient than C8 in this respect. Peripheral neuropathy of LCHADD and MTPD is described as axonal neuropathy with possible secondary demyelination [ 56 ]. Our previous study demonstrated increased HEX levels in LCHADD fibroblasts [ 19 ]; if disruption of sphingolipid metabolic flux were to occur also in vivo, it would be indicative of a possible derangement of proper myelination, thereby affecting neurological function [ 57 ].…”

Reversible sensory neuropathy in mitochondrial trifunctional protein deficiency

“…1,3 The neuropathic phenotype is heterogeneous comprising isolated sensory, 4,5 isolated motor 1 and sensorimotor forms. 1 Neuropathy is usually considered irreversible. 3 We recently outlined the clinical spectrum of peripheral neuropathy in a cohort of 8 LCHAD deficient and 11 MTP-deficient patients.…”