Disorders of muscle lipid metabolism: Diagnostic and therapeutic challenges

doi:10.1016/j.nmd.2010.06.018

Neuromuscular Disorders

Volume 20, Issue 11, November 2010, Pages 693-700

https://doi.org/10.1016/j.nmd.2010.06.018 Get rights and content

Abstract

Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or fatty acid β-oxidation. Three main diseases leading to permanent muscle weakness are associated with severe increased muscle lipid content (lipid storage myopathies): primary carnitine deficiency, neutral lipid storage disease and multiple acyl-CoA dehydrogenase deficiency. A moderate lipidosis may be observed in fatty acid oxidation disorders revealed by rhabdomyolysis episodes such as carnitine palmitoyl transferase II, very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein deficiencies, and in recently described phosphatidic acid phosphatase deficiency. Respiratory chain disorders and congenital myasthenic syndromes may also be misdiagnosed as fatty acid oxidation disorders due to the presence of secondary muscle lipidosis. The main biochemical tests giving clues for the diagnosis of these various disorders are measurements of blood carnitine and acylcarnitines, urinary organic acid profile, and search for intracytoplasmic lipid on peripheral blood smear (Jordan’s anomaly). Genetic analysis orientated by the results of biochemical investigation allows establishing a firm diagnosis. Primary carnitine deficiency and multiple acyl-CoA dehydrogenase deficiency may be treated after supplementation with carnitine, riboflavine and coenzyme Q10. New therapeutic approaches for fatty acid oxidation disorders are currently developed, based on pharmacological treatment with bezafibrate, and specific diets enriched in medium-chain triglycerides or triheptanoin.

Introduction

Disorders of lipid metabolism affecting muscle may involve endocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or β-oxidation. The pathological hallmark of some of these diseases is an increased neutral lipid content, which may be observed on muscle biopsies specimen with the specific staining of Sudan black or oil red O techniques by optic microscopy. In a normal muscle, lipid content takes the aspect of small droplets which concentration and size are usually higher in type 1 fibres than in type 2 fibres [1]. The average lipid fraction of the fibre volume is estimated to less than 0.2% [2], but most pathologists evaluate this lipid content subjectively, making therefore difficult to determine a clear-cut level of lipid accumulation which could be considered accurately as “pathological”. The term of lipid storage myopathies is often used when the accumulation of lipid droplets in muscle fibres is uppermost, and associated with a vacuolated appearance on routine histological stains such as hematoxylin and eosin or Gomori trichrome. Conversely, lipid metabolism disorders are inconstantly leading to a muscle lipidosis, and therefore awareness of their clinical features and main biological anomalies are essential for establishing accurate diagnosis. Muscle lipid metabolism having been comprehensively described previously [2], [3], [4], [5], [6], we provide here a scheme of the major enzymatic pathways involved in currently known metabolic myopathies involving lipid metabolism (Fig. 1, Fig. 2). In this paper, we describe the main muscle disorders to consider in this context, according to the severity of pathological findings. Although some of these disorders are extremely rare, their diagnostic approach may be considerably improved considering the clinical features, the importance of lipid accumulation, and results of routine biochemical analysis such as plasma carnitine and acylcarnitine profile.

Section snippets

Primary carnitine deficiency (PCD)

PCD (also called carnitine uptake defect or systemic carnitine deficiency) is the most classical cause of lipid storage myopathy but remains exceptional [7]. This disease is caused by a defect in the high-affinity plasma membrane sodium-dependent carnitine transporter (OCTN2) in several tissues, including, muscle, heart, and kidney, but not liver. This induces increased loss of carnitine in urine and decreased concentration in plasma, heart and skeletal muscle. The most common phenotype is

Carnitine palmitoyl transferase II (CPT II) deficiency

CPT II was the first inherited defect of FAO to be identified [25]. Three different clinical phenotypes are associated with a defect in CPT II according to the age of onset, but muscular symptoms (recurrent myoglobinuria, muscle aching and stiffness on long-term exercise) occur mainly in the juvenile-adult onset form. This myopathic form is probably the most frequent cause of recurrent myoglobinuria in young adults. Episodes of myalgias and rhabdomyolysis are triggered by prolonged exercise,

Diagnostic strategy of muscle lipidosis

Although there is no clear-cut definition of a muscle lipidosis due to the subjective analysis, pathologists are generally able to determine if a biopsy shows a massive or a moderate lipidosis (Fig. 3). When a massive lipidosis is present, three lipid storage myopathies should be envisaged: primary carnitine deficiency, multiple acyl-CoA dehydrogenase deficiency, and neutral lipid storage disease (with or without ichthyosis). The main biochemical exams allowing orientation towards a precise

Treatment

Proposed treatment strategies for lipid metabolism disorders include: (1) avoidance of exacerbating factors, (2) carnitine supplementation, (3) riboflavin treatment and (4) dietary modifications (medium-chain triglycerides and triheptanoin).

Avoidance of exacerbation factors still plays a large part in the management of these diseases. In children with FAO defects, fasting and infections are the major causes of metabolic decompensation and rhabdomyolysis. Patients need to avoid fasting and

Conclusion and perspectives

Many patients in whom muscle biopsy shows lipidosis remain without diagnosis despite thorough investigations [9]. This low rate of diagnosis of muscle lipidosis could be explained by the following possibilities: (1) the physiological and inter-individual variability of lipid accumulation within muscle fibres limiting the accuracy of the pathological diagnosis; (2) the possibility of still unknown metabolic diseases; and (3) secondary increase of lipid in muscle due to other diseases without

Acknowledgments

We thank Dr. Jean-Marie Mussini (CHU de Nantes, France) for providing muscle biopsy analysis of patient with neutral lipid storage disease. We thank Pr Pascale De Lonlay (CHU Necker-Enfants-Malades, Paris, France), Dr. Norma Romero (Myology Institute, Paris, France) and Mrs. Emmanuelle Lacene (Myology Institute, Paris, France) for providing muscle biopsy analysis of a patient with LIPIN deficiency.

References (63)

P. Laforêt et al.
162nd ENMC international workshop: disorders of muscle lipid metabolism in adults 28–30 November 2008, Bussum, The Netherlands
Neuromuscul Disord
(2010)
L.A. Schimmenti et al.
Expanded newborn screening identifies maternal primary carnitine deficiency
Mol Genet Metab
(2007)
C. Lefèvre et al.
Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin–Dorfman syndrome
Am J Hum Genet
(2001)
C. Bruno et al.
Clinical et genetic characterization of Chanarin–Dorfman syndrome
Biochem Biophys Res Commun
(2008)
A. Ohkuma et al.
Distal lipid storage myopathy due to PNPLA2 mutation
Neuromuscul Disord
(2008)
F. Campagna et al.
Novel mutations in the adipose triglyceride lipase gene causing neutral lipid storage disease with myopathy
Biochem Biophys Res Commun
(2008)
W.-C. Liang et al.
ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency
Neuromuscul Disord
(2009)
S. Corti et al.
Clinical features and new molecular findings in carnitine palmitoyltransferase II (CPTII) deficiency
J Neurol Sci
(2008)
C. Vianey-Saban et al.
Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients
Clin Chim Acta
(1998)
P. Laforêt et al.
Diagnostic assessment and long-term follow-up of 13 patients with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency
Neuromuscul Disord
(2009)

T. Tyni et al.

Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation

Neuromuscul Disord

(1996)

A. Zeharia et al.

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood

Am J Hum Genet

(2008)

I. Tein et al.

Short-chain acyl-CoA dehydrogenase gene mutation (c.319C > T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin

Mol Genet Metab

(2008)

G.M. Enns et al.

Mitochondrial respiratory chain complex I deficiency with clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency

J Pediatr

(2000)

K.G. Sim et al.

Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those from patients with mitochondrial fatty acid beta-oxidation disorders

Metabolism

(2002)

V. Dubowitz et al.

Muscle biopsy. A practical approach

(2007)

S. Di Donato et al.

Disorders of lipid metabolism

J. Vockley et al.

Diagnosis and management of defects of mitochondrial beta-oxidation

Curr Opin Clin Nutr Metab Care

(2002)

C. Angelini

Disorders of lipid metabolism

C. Bruno et al.

Lipid storage myopathies

Curr Opin Neurol

(2008)

A.C. Engel et al.

Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy. A new syndrome

Science

(1973)

A. Ohkuma et al.

Clinical and genetic analysis of lipid storage myopathies

Muscle Nerve

(2009)

W.R. Treem et al.

Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts

N Engl J Med

(1988)

I. Tein et al.

Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy

Pediatr Res

(1990)

J. Nezu et al.

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter

Nat Genet

(1999)

I. Chanarin et al.

Neutral-lipid storage disease: a new disorder of lipid metabolism

Br Med J

(1975)

J. Fischer et al.

The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy

Nat Genet

(2007)

M. Akiyama et al.

Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy

Muscle Nerve

(2007)

R.K. Olsen et al.

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Brain

(2007)

K. Gempel et al.

The myopathic form of coenzyme Q deficiency is caused by mutations in the electron-transferring flavoprotein dehydrogenase (ETFDH) gene

Brain

(2007)

B. Wen et al.

Riboflavin responsive lipid storage myopathy caused by ETFDH gene mutations

J Neurol Neurosurg Psychiatry

(2010)

Cited by (85)

The presence of white cell Jordan's anomaly in multiple Acyl-CoA dehydrogenase deficiency: A case report and implications for clinical practice
2024, Clinical Biochemistry
Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), also known as Glutaric Aciduria Type II, is an exceptionally rare autosomal recessive genetic disorder that disrupts the metabolism of fatty acids, amino acids, and choline. It presents with a wide range of clinical manifestations, from severe neonatal-onset forms to milder late-onset cases, with symptoms including metabolic disturbances and muscle weakness. Jordan's anomaly is a distinctive morphological feature found in peripheral blood white cells and is typically associated with Neutral Lipid Storage Disease (NLSD).
In our case report, the patient initially presented with symptoms of vomiting, abdominal pain, and altered consciousness. The presence of white cell Jordan's anomaly was detected in the blood smear. Subsequent serum tests revealed elevated levels of transaminases, creatine kinase, uric acid, and multiple acylcarnitines, while blood glucose and free carnitine levels were notably reduced. High-throughput sequencing confirmed heterozygous pathogenic variants in the electron-transferring flavoprotein dehydrogenase (ETFDH) gene, leading to the conclusive diagnosis of MADD. Following a three-month treatment regimen involving high-dose vitamin B2, coenzyme Q10, and other supportive interventions, the patient exhibited significant clinical improvement, ultimately resulting in discharge.
The identification of Jordan's anomaly in a pediatric patient with late-onset MADD sheds light on its broader implications within the realm of lipid storage myopathies. The significance of this finding extends beyond its conventional association with NLSD, challenging the notion of its exclusivity. This novel observation serves as a compelling reminder of the diagnostic significance this morphological abnormality holds, potentially revolutionizing diagnostic practices within the field.
Clinical and biochemical footprints of inherited metabolic disorders: X. Metabolic myopathies
2022, Molecular Genetics and Metabolism
Metabolic myopathies are characterized by the deficiency or dysfunction of essential metabolites or fuels to generate energy for muscle contraction; they most commonly manifest with neuromuscular symptoms due to impaired muscle development or functioning. We have summarized associations of signs and symptoms in 358 inherited metabolic diseases presenting with myopathies. This represents the tenth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.
Fatty acids impact sarcomere integrity through myristoylation and ER homeostasis
2021, Cell Reports
Citation Excerpt :
For example, fat deficiency has been known to limit female reproductive development and cause muscle loss to improve starvation survival (Lipina and Hundal, 2017; Reznick and Braun, 1987; Tang and Han, 2017). In addition, abnormal FA metabolism has been linked to certain muscular diseases (Laforêt and Vianey-Saban, 2010; Lipina and Hundal, 2017; Saini-Chohan et al., 2012). However, the mechanisms by which FAs affect muscle integrity, and the potential role of lipid-sensing systems in these processes, remain to be investigated.
Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal development and tissue maintenance, but our understanding of the underlying mechanisms is limited. We investigated whether and how FA abundance affects muscle integrity using Caenorhabditis elegans. We show that reducing the overall FA level by blocking FA biosynthesis or inhibiting protein myristoylation leads to disorganization of sarcomere structure and adult-onset paralysis. Further analysis indicates that myristoylation of two ARF guanosine triphosphatases (GTPases) critically mediates the effect of FA deficiency on sarcomere integrity through inducing endoplasmic reticulum (ER) stress and ER unfolded protein response (UPR^ER), which in turn leads to reduction of the level of sarcomere component PINCH and myosin disorganization. We thus present a mechanism that links FA signal, protein myristoylation, and ER homeostasis with muscle integrity, which provides valuable insights into the regulatory role of nutrients and ER homeostasis in muscle maintenance.
Sensory neuronopathy as a major clinical feature of mitochondrial trifunctional protein deficiency in adults
2020, Revue Neurologique
Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor.
To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy.
Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy (“ganglionopathy”). All patients harbored at least one c.1528G>C mutation.
We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.
Metabolic, mitochondrial and toxic myopathies
2019, Medicine (Spain)
Las miopatías metabólicas y mitocondriales son trastornos hereditarios que tienen en común ser secundarias a un defecto en la obtención de energía en forma de ATP desde los nutrientes. Pueden estar alteradas las vías del metabolismo de los hidratos de carbono o los lípidos o la fosforilación oxidativa mitocondrial, que es la vía final común del metabolismo aeróbico. Se pueden manifestar de forma episódica o con debilidad muscular de curso progresivo. La historia clínica es el pilar fundamental a partir del cual dirigir el diagnóstico diferencial y, en ella, deberá incluirse siempre un interrogatorio detallado sobre los antecedentes de exposición a fármacos. Muchos de ellos pueden tener efectos adversos sobre el músculo, con síntomas similares a los característicos de los trastornos metabólicos musculares. El diagnóstico definitivo debe ser molecular, puesto que además de asegurar un correcto asesoramiento genético a las familias, permitirá desde ya o en el futuro ofrecer un tratamiento personalizado.
Metabolic and mitochondrial myopathies are inherited disorders characterized by incompetence to provide energy substrate (ATP) from nutrients. Both carbohydrate or lipid metabolism or mitochondrial oxidative phosphorylation, (final common pathway for aerobic metabolism), may be altered. Clinically can appear like episodes besides to progressive muscle weakness. Differential diagnosis is based on clinical history, including detailed search for history of exposure to drugs, that might have adverse effects similar to muscle metabolic disorders. Molecular diagnosis allows establishing definitive diagnosis, as well as to perform genetic counseling and to provide a personalized treatment, now or in the future.
Neutral lipid storage disease with myopathy and dropped head syndrome. Report of a new variant susceptible of treatment with late diagnosis
2018, Journal of Clinical Neuroscience
Neutral lipid storage disease with myopathy (NLSDM) is characterized by the accumulation of cytoplasmic triglyceride droplets in various tissues; this very rare condition is caused by mutations in the PNPLA2 gene, susceptible to specific pharmacological management that decreases clinical progression. We describe the clinical and biochemical characteristics of a Colombian patient with a previously unreported homozygous mutation in the PNPLA2 gene with a difficult to manage disease, who was diagnosed late by advances in molecular techniques.

View all citing articles on Scopus

View full text

ReviewDisorders of muscle lipid metabolism: Diagnostic and therapeutic challenges

Abstract

Introduction

Section snippets

Primary carnitine deficiency (PCD)

Carnitine palmitoyl transferase II (CPT II) deficiency

Diagnostic strategy of muscle lipidosis

Treatment

Conclusion and perspectives

Acknowledgments

Neuromuscul Disord

Mol Genet Metab

Am J Hum Genet

Biochem Biophys Res Commun

Neuromuscul Disord

Biochem Biophys Res Commun

Neuromuscul Disord

J Neurol Sci

Clin Chim Acta

Neuromuscul Disord

Neuromuscul Disord

Am J Hum Genet

Mol Genet Metab

J Pediatr

Metabolism

Muscle biopsy. A practical approach

Disorders of lipid metabolism

Diagnosis and management of defects of mitochondrial beta-oxidation

Curr Opin Clin Nutr Metab Care

Disorders of lipid metabolism

Lipid storage myopathies

Curr Opin Neurol

Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy. A new syndrome

Science

Clinical and genetic analysis of lipid storage myopathies

Muscle Nerve

Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts

N Engl J Med

Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy

Pediatr Res

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter

Nat Genet

Neutral-lipid storage disease: a new disorder of lipid metabolism

Br Med J

The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy

Nat Genet

Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy

Muscle Nerve

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Brain

The myopathic form of coenzyme Q deficiency is caused by mutations in the electron-transferring flavoprotein dehydrogenase (ETFDH) gene

Brain

Riboflavin responsive lipid storage myopathy caused by ETFDH gene mutations

J Neurol Neurosurg Psychiatry

Review
Disorders of muscle lipid metabolism: Diagnostic and therapeutic challenges