Multisystem Involvement in Chinese Patients with Neuromyopathic Phenotype of Mitochondrial Trifunctional Protein Deficiency
Mitochondrial trifunctional protein (MTP) is a multienzyme complex that plays a crucial role in the mitochondrial beta-oxidation of long-chain fatty acids. Structurally, MTP is composed of four alpha-subunits and four beta-subunits, encoded by the HADHA gene (OMIM 600890) and HADHB gene (OMIM 143450), respectively. Mutations in either of these genes can lead to varying degrees of MTP activity decline, resulting in three distinct clinical phenotypes: a severe neonatal-onset phenotype, a hepatic infantile-onset phenotype, and a neuromyopathic phenotype with later onset. The neuromyopathic phenotype is the mildest form, characterized by myopathy, sensorimotor neuropathy, and recurrent rhabdomyolysis. To date, only 33 cases of this phenotype have been reported worldwide, with only two cases documented in China. This article describes three early-onset Chinese cases that not only exhibited neuromyopathy and rhabdomyolysis but also involved the central nervous system (CNS), which is uncommon in this phenotype.
The first two patients were sisters born to non-consanguineous healthy parents. Patient 1, a 13-year-old girl, had slightly delayed early motor development milestones. She began walking independently at 21 months but was always reluctant to do so. From the age of five, she presented with gait abnormalities and muscle weakness, which gradually progressed. At age ten, she was referred to the clinic with a history of mild mental retardation and cataract. Although she had complained of blurred vision since age five, she was diagnosed with cataract at eight and underwent bilateral intraocular lens implantation. Physical examination revealed distal muscle weakness, tendon areflexia, and strephenopodia. Laboratory tests showed significantly elevated creatine kinase (CK) levels (>8000 IU/L, reference range: 45–170 IU/L) and moderately increased transaminase levels. Parathyroid hormone (PTH) and serum electrolyte levels were normal. Routine blood acylcarnitines testing indicated a mild decrease in free-carnitine levels and a slight increase in long-chain 3-hydroxy acylcarnitine species. Urine organic acid analysis was normal. A brain computed tomography scan revealed calcifications in the bilateral basal ganglia and subcortical white matter of the frontal and parietal lobes. Electromyogram (EMG) showed high-amplitude and long-duration motor unit potentials, and nerve conduction velocity tests indicated reduced amplitude in the compound motor action potential, supporting neurogenic injury. A muscle biopsy from the left biceps brachii muscle showed fiber type grouping and type 1 fiber predominance, suggesting peripheral neuropathy. Oil red O staining showed a mild increase in fatty droplets, with no ragged red fibers or glycogen aggregates observed. Whole exome sequencing identified a homozygous known mutation c.1175C>T (p.A392V) in the HADHB gene, which is reportedly pathogenic. Both parents were carriers. The patient was diagnosed with the neuromyopathic phenotype of MTP deficiency and treated with a low dose of L-carnitine and a special diet limiting long-chain fatty acids and supplementing medium-chain fatty acids. At follow-up, she presented with soy urine after a long walk at age 11, considered rhabdomyolysis, but did not experience it again.
Patient 2, the younger sister of Patient 1, had mild motor development delay and exercise intolerance since early childhood. At age four, she showed very slight muscle weakness, with normal CK levels. Due to symptoms similar to her sister, Sanger sequencing of HADHB was performed, confirming the same c.1175C>T mutation. As her condition was mild, her parents did not strictly follow treatment recommendations. At age five, she developed rhabdomyolysis and lethargy during a flu-induced high fever. On the way to the hospital, she suffered cardiac arrest. Despite successful resuscitation, she fell into a coma and died three days later.
Patient 3 had previously been reported with a homozygous missense mutation c.739C>T (p.R247C) in HADHB. She developed progressive muscle weakness, infection-induced lethargy, exercise-induced muscle pain, and intermittent hyperCKemia from age three. Blood acylcarnitines analysis, EMG, and muscle biopsy results were similar to Patient 1. At age eight, she was genetically diagnosed with MTP deficiency. At follow-up, she presented with myalgia and soy-colored urine after fever at age 11, diagnosed as rhabdomyolysis based on markedly elevated CK and myoglobinuria. She developed rhabdomyolysis 1 to 3 times a year. Two months ago, she developed coma and respiratory failure during fever, requiring non-invasive ventilation. She has gradually recovered but has lost the ability to walk, although her intelligence remains unaffected.
MTP, located in the inner mitochondrial membrane, catalyzes the last three steps of beta-oxidation of long-chain fatty acids. In MTP deficiency, stress such as fever or exercise can lead to organ dysfunction, particularly in high-energy-demand organs. The neuromyopathic phenotype typically involves muscles and peripheral nerves. However, the cases in this study also exhibited CNS and eye manifestations. Patients 2 and 3 experienced infection-induced lethargy, previously unreported in the neuromyopathic phenotype but common in the neonatal phenotype. Lethargy may be related to insufficient brain energy supply or brain injury caused by abnormal metabolic substrates.
Patient 1 showed intracranial calcifications and cataracts, rare complications of MTP deficiency. Hypoparathyroidism has been reported in three MTP deficiency patients, potentially explaining calcifications and cataracts. However, serum calcium, phosphorus, and PTH levels were normal, providing no evidence for hypoparathyroidism. Two Japanese siblings with the same A392V mutation as Patients 1 and 2 presented with infantile-onset hypoparathyroidism and peripheral neuropathy, with parathyroid function normalizing with age. Adjacent mutations N389D and F398L have also been associated with hypoparathyroidism and intracranial calcification, respectively. Mutations in this HADHB region may lead to MTP deficiency with symptomatic or insidious hypoparathyroidism.
Despite sharing the same gene, Patient 2 had a more severe clinical condition than Patient 1. The poor prognosis of Patient 2 may be due to severe infection and non-compliance with treatment.
In conclusion, this study describes multisystem involvement in three Chinese patients with the neuromyopathic phenotype of MTP deficiency. In addition to nerve and muscle involvement, this phenotype also affects the CNS and possibly the parathyroid glands.
doi.org/10.1097/CM9.0000000000000805
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