Neurometabolic disorder with neuromuscular manifestation

Last update Dec 1 Thanes Termglinchan M.D. Contents Back  1. Overview neurometabolic disorders: pathophysiology, neurological symptoms 2. Categories of neurometabolic disorder 3. Paediatric vs. Adult Phenotypes 4. Neuropathy manifestation in neurometabolic disorder • Acute porphyria • Metachromatic Leukodystrophy (MLD) • Adrenoleukodystrophy/ Adrenomyeloneuropathy • Globoid-Cell Leukodystrophy (Krabbe’s Disease) • Tangier Disease • Bassen-Kornzweig Disease (Abetalipoproteinemia) • Fabry’s disease (a-galactosidase deficiency) • Refsum disease • Cerebrotendinous xanthomatosis Contents

5. Myopathy manifestation in neurometabolic disorder • Clinical manifestation • Glycolysis and glucogenolysis • Lipid storage disease • Mitochondrial disorder 6. Summary nerve and muscle in neurometabolic disorder Pattern and clinical manifestation • metabolic causes of peripheral neuropathy • metabolic causes of myopathy Neurometabolic disorder

Key feature: • Mostly are presented in newborns and infants • Neurological or psychiatric manifestations are the prominent signs and symptoms • A complex, heterogenous group of disorders and multi systems diseases • Rapid life-threatening deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades. • Triggered by fasting, exercise, fever, catabolic circumstances or post partum • Nerve or muscle dysfunction are one feature of neurometabolic disorder Pathophysiology

• Major foodstuffs are converted to energy or cellular and tissue building blocks and final products • The mechanisms by which foodstuffs and products are degraded to be excreted • These include: • Mechanisms involving absorption and modification of vitamins and minerals • Mechanisms for degrading molecules to provide energy or to be excreted • Mechanisms for making acetyl-coenzyme A, nonessential amino acids, cholesterol, long-chain fatty acids, prostaglandins, and the complex lipids

Johan Lundgren Categories of neurometabolic disorder

1. Disorders of Energy Metabolism: 2. Disorders of Lipid Metabolism 3. Intoxication Syndromes 4. Disorders of Neurotransmitter Metabolism 5. Metal Storage Disorders

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Neurometabolic Presentations in Adults

• Psychiatric Disorders • Cerebellar Ataxia • Encephalopathies/Comas • Epilepsy • Leukoencephalopathies • Peripheral Neuropathies • Strokes and Pseudostrokes • Myopathy • Spastic Paraparesis • Others • Movement Disorders

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases, Categories of neurometabolic disorder

Categories Clinical presentation Diseases

1. Disorders of Energy Acute: acute optic neuropathy, acute cerebellar ataxia, Pyruvate dehydrogenase deficiency, Krebs cycle Metabolism: pseudo-strokes or status epilepticus. deficiencies, β-oxidation defects and disorders Chronic: muscles, cerebellum, basal ganglia involving co-factors such as ETF deficiency, Respiratory chain disorder: 1⁰ or (parkinsonism, dystonia), cortex (epilepsy, myoclonus) or vitamin E deficiency, biotinidase deficiency, 2⁰ the peripheral nervous system (axonal polyneuropathy). biotin-responsive basal ganglia disease, creatine LSD, GSD deficiency syndromes and coenzyme Q synthesis Less: spastic paraparesis defects. Leigh syndrome 2. Disorders of Lipid Metabolism Spastic paraparesis Sphingolipidoses: (Krabbe disease, Leukodystrophy and demyelinating polyneuropathy metachromatic leukodystrophy, Niemann Pick A Interfering with myelin Splenomegaly: Niemann-Pick B and C, Gaucher disease and B, Fabry disease and Gaucher disease), formation or maintenance. and Tangier disease. Peroxisomal disorders: Lysosomal storage disease (adrenomyeloneuropathy, Refsum disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders) Sterols disorders: (cerebrotendinous xanthomatosis, Niemann-Pick C, spastic paraplegia type 5 and Tangier disease) 3. Intoxication Syndromes Metabolic crisis Porphyrias, urea cycle defects, organic acidurias, Leukoencephalopathies, epilepsy, psychiatric disorders or aminoacidopathies and homocysteine Spastic paraparesis remethylation defects. Neuropathy Categories of neurometabolic disorder

Categories Clinical presentation Diseases

4. Disorders of Neurotransmitter Dopamine deficiency: dystonia, parkinsonism, oculogyric Dopa-responsive dystonia or parkinsonism Metabolism crisis), Hyperekplexia defects in the synthesis of Noradrenergic deficiency: ptosis, myosis, hypotension serotonin and dopamine Serotonin deficiency sleep disturbance, dysthermia, behavioural disturbance. Defective inhibitory glycinergic neurotransmission (Hyperekplexia)

5. Metal Storage Disorders Copper metabolism Wilson disease Iron metabolism NBIA Manganese metabolism: polycythemia, cirrhosis SLC30A10 mutation Paediatric vs. Adult Phenotypes Differences Between Paediatric and Adult Phenotypes

Disease Classic presentation in childhood Adult-onset forms

Biotinidase deficiency Muscular hypotonia, lethargy, grand mal Bilateral optic atrophy, spastic and myoclonic seizures, ataxia, stridor, paraparesis, motor neuropathy skin lesions Fabry disease Crises of acroparaesthesia Strokes, vertigo, cardiomyopathy, hearing loss, proteinuria Coenzyme Q10 deficiency Leigh syndrome, myoglobinuria, Cerebellar ataxia, myopathy encephalopathy Cerebrotendinous xanthomatosis Mental retardation, chronic diarrhea, Tendon xanthomas, cerebellar ataxia, epilepsy, juvenile cataract, neonatal spastic paraparesis, dementia, psychiatric cholestasis signs Fatty acid β-oxidation defects Non-ketotic hypoglycaemia, Encephalopathy (MCAD),rhabdomyolysis, cardiomyopathy, liver disease, Proximal myopathy rhabdomyolysis, peripheral neuropathy, retinitis pigmentosa (LCHAD) Differences Between Paediatric and Adult Phenotypes

Disease Classic presentation in childhood Adult-onset forms

MERRF Myoclonic epilepsy, generalized epilepsy, Cerebellar ataxia, hearing loss, peripheral Cerebellar ataxia neuropathy, lipomatosis Metachromatic leukodystrophy Progressive gait problems, hypotonia, Psychiatric form: »psychosis-like features peripheral neuropathy, spasticity in all four (mimics schizophrenia), cognitive decline« limbs, optic atrophy, cerebellar ataxia Motor form: »spastic paraparesis, cerebellar ataxia, dystonia, demyelinating polyneuropathy« Glycogenosis type IV (glycogen Neuromuscular form, combined hepatic and Polyglucosan body disease: spastic branching enzyme deficiency) myopathic form paraparesis, peripheral neuropathy, leukoencephalopathy with spinal cord atrophy GM2 gangliosidosis Motor weakness, visual loss, progressive Psychosis, lower motor neuron disease, spasticity, macular cherry red spot, epilepsy cerebellar ataxia, dystonia, sensory neuronopathy Krabbe disease Progressive encephalopathy, hyperaesthesia, Spastic paraparesis with or without peripheral tonic spasms, signs of peripheral neuropathy, neuropathy, specific leukoencephalopathy blindness, loss of bulbar function, seizures involvingcortico-spinal tracts Neuropathy manifestation in neurometabolic disorder Clinical context

• Misdiagnosis as “Charcot-Marie-Tooth disease” • Acute, relapsing or long-standing chronic • Demyelination, axonopathy, multiple mononeuropathy, motor neuronopathy, DRG, small fiber neuropathy or sensory ataxia • Multi-systems involvement: leukoencephalopathy, ataxia, pyramidal signs, psychiatric or visual signs) or with systemic disease (skin problems, xanthomas, splenomegaly, cataract) • Genetic: AD,AR, X-linked and maternal transmission Two main groups of metabolic diseases

• Lipid storage disorders: defective myelination on both peripheral and central myelin • Leukoencephalopathy • Energy metabolism defects • Axonal peripheral neuropathies • Associated with cerebellar ataxia in the case of respiratory chain disorders Mimic common neuropathy

Type of neuropathy Common conditions Neurometabolic diseases Painful neuropathy Diabetes neuropathy, HIV-associated Fabry disease, Tangier disease, GM2 peripheral sensory neuropathy (HIV-SN) gangliosidosis, porphyria.

Relapsing-remitting multifocal MADSAM Tangier disease sensory motor demyelination Acute polyneuropathy Guillain-Barré syndrome Porphyria, pyruvate dehydrogenase deficiency, acute exacerbations of Refsum disease or untreated tyrosinaemia type 1. Motor neuronopathy Spinal muscular atrophy, progressive muscular Late-onset Tay Sachs disease atrophy Dorsal root ganglia Paraneoplastic, Sjogren syndrome, POLG mutations

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Neuropathy manifestation in common neurometabolic diseases • Porphyria: hepatic porphyria • Leukodystrophies: MLD, AML, Krabbe’s disease • Lipoprotein deficiencies: alphalipoprotein deficiency, abetalipoproteinemia • Fabry’s disease (a-galactosidase deficiency) • Phytanic acid storage diseases (Refsum disease) • Cerebrotendinous xanthomatosis (cholestanolosis) • Niemann-Pick disease (sphingomyelin lipidosis) Porphyria Interruption of heme biosynthesis: liver and bone marrow Pathogenesis: decreased heme production and accumulation of porphyrin precursors and porphyrins in various tissues. • Axonal degeneration of peripheral nerves and central chromatolysis Neuropathy: only hepatic porphyrias • Acute intermittent porphyria (AIP) • Variegate porphyria (VP) • Hereditary coproporphyria (HCP) • Aminolevulinic acid (ALA) dehydrase deficiency. The heme biosynthesis pathway

Z. Karim et al.2015 Genetic classification of the porphyrias Porphyria Enzyme Inheritance Classification Clinical features

ALA dehydratase ALAD AR Acute hepatic Acute neurovisceral deficiency porphyria(ADP)

Acute intermittent HMBS AD Acute hepatic Acute neurovisceral porphyria (AIP): MC Incomplete penetrance (10%) Hereditary CPOX AD Acute hepatic Acute neurovisceral (100%) coproporphyria (HCP) Photosensitivity (20%)

Variegate porphyria PPOX AD Acute hepatic Acute neurovisceral (50%) (VP) Photosensitivity (80%)

N.G. Simon, G.K. Herkes / Journal of Clinical Neuroscience 18 (2011) Neuropathy 1st Autonomic neuropathy: parasympathetic and sympathetic dysfunction splanchnic autonomic neuropathy • Tachycardia, HT or hypotension • Abdominal pain with or without constipation, Diarrhea, nausea and vomiting Peripheral neuropathy(3-75 days after abdominal symptom): ANS- >polyneuropathy (axonal > demyeline), DRG, small fibers. • Predominantly motor axonal neuropathy • Proximal muscles are predominantly affected in 80% of patients and onset is in the upper limbs in 50%. • Sensory (60%): 50% bathing-trunk, glove and stocking • Cranial neuropathy 75%: 7, 10, 5, 12, 11, 3

N.G. Simon, G.K. Herkes / Journal of Clinical Neuroscience 18 (2011) 1147–1153 Accumulation of heme synthesis substrates in the blood and urine

Hereditary tyrosinemia, type I dysfunction of fumaryl acetoacetate hydrolase leads to accumulation of 4,6-dioxoheptanoic acid, a potent inhibitor of ALA dehydrase, and thus mimics ALA dehydrase deficiency.

genereviews.org Management in symptomatic porphyrias Porphyria Treatment

ALA dehydratase deficiency Prevent attack: avoid trigger porphyria(ADP) Supportive treatment Avoidance of precipitation factor, antiemetic, opiates and chlorpromazine, adequate fluid intake, Adequate calories: orally as carbohydrate-rich food supplements (55-60%) or normal Acute intermittent porphyria (AIP) salinewith 5% dextrose.

Specific treatment is carbohydrate(400 g/day) or 10-20% glucose in NSS for 2 liters/day, Hereditary coproporphyria (HCP) Heme arginate; infusion Normosang®(25 mg/day × 4) Liver Transplantation

Variegate porphyria (VP) Monitor: plasma PBG levels

New therapy: Givosiran, a subcutaneously administered GalNAc-conjugated RNAi therapeutic targeting hepatic ALAS1 to assess prevention of attacks are in progress. NCT03338816, First Posted: November 9, 2017

Z. Karim et al. Factors Known to Trigger or Exacerbate Acute Porphyric Attacks http://www.drugs porphyria.org Drugs and chemicals, especially • Excess alcohol • Barbiturates • Estrogens • Hydantoins • Progestagens • Sulfonamides • All drugs that are suicide substrates or potent inducers of cytochrome P450 Dieting; fasting; deficiency of carbohydrate intake (gastric bypass surgery) Exhaustion—emotional or physical Intercurrent acute illnesses Cigarette smoking

S. Besur et al. ACUTE PORPHYRIAS, 2015 Leukodystrophies

Metachromatic Leukodystrophy (MLD) Adrenoleukodystrophy (ALD)/Adrenomyeloneuropathy (AMN) Globoid-Cell Leukodystrophy (Krabbe’s Disease) Metachromatic Leukodystrophy (MLD)

• Lysosomal storage disorders (lipidoses) affecting myelin. • Demyelination in the central and peripheral nervous system • Accumulation of galactosyl sulfatide (cerebroside sulfate) in glia, Schwann cells, and macrophages. • Autosomal recessive, the ARSA gene encoding arylsulfatase A Onset: Late-infantile, juvenile, and adult-onset forms. A deficiency of arylsulfatase A + the accumulation of sulfatide in the central and peripheral nervous system. Metachromatic Leukodystrophy (MLD)

Onset form Age of onset Clinical presentations Late-infantile 30 months hypotonic neuropathic form, ataxia, limb pain, dementia, and dysarthria. quadriplegia 50-60% or decerebrate rigidity, blindness, deafness, seizures, and myoclonic jerks (2 O allele)

Juvenile 3-20 year-old reduced school performance, 20-30% clumsiness, dysarthria, seizures, and behavioral problems (1 O, 1 R allele)

Adult-onset Any age beyond psychosis, with poor job performance, alcoholism, and emotional instability. Ataxia and 15-20% puberty spasticity (2 R allele) A mild peripheral neuropathy: ↓ motor CV Variants form ? Adult-onset isolated demyelinating neuropathy, Multifocal nonuniform slowing Mirroring chronic inflammatory demyelinating neuropathy

O allele: no enzyme, R allele: residual enzyme Pseudoarylsulfatase deficiency states: reduced level of arylsulfatase A without disease P.K. Richardson and S.T. Demarest

Metachromatic Leukodystrophy (MLD) Diagnosis: adult onset form. • MRI brain: bilateral symmetric abnormal T2 signal hyperintensity starting in the corpus callosum and then involving the periventricular white matter (the rostrum and frontal white matter)

Reduced arylsulfatase A levels in serum (R/oPseudo deficiency) Abnormal urinary sulfatide excretion or of metachromatic lipid deposits in nervous tissue Tigroid-pattern: radiating stripes with bands of normal signal intensity within the abnormal white matter. NCS: demyelination, CV 10-20 m/s, reduced SNAP Nerve biopsy: Segmental demyelination-remyelination and small onion bulbs

D.F. van Rappard et al. Management

• No curative treatment Treatment that improved neurological function • Autologous stem cells, combined therapy with bone marrow and mesenchymal stem cell transplant. • NAA levels by magnetic resonance spectroscopy correlate with function and can be used to monitor disease progression. Adrenoleukodystrophy/ Adrenomyeloneuropathy

• An X-linked recessive disorder, ABCD1 gene: primarily the nervous system myelin, the adrenal cortex, and the Leydig cells of the testes. • The pathologic substance, very long-chain fatty acids (VLCF), can be detected in several organs, plasma, and cultured skin fibroblasts • Pathogenesis: defect the transport protein facilitates b-oxidation of long-chain fatty acids  accumulation of lipid material (unbranched a chain length of 24– 30 carbons) in many cells toxic to oligodendrocytes and to mitochondrial function • Diagnosis: elevated levels of very long-chain fatty acids (VLCF), C26 fatty acid or elevated C26:C22 ratios in plasma or skin fibroblasts. • Investigation: electrolytes, serum testosterone, and cortisol. • NCS: mixed demyelination and axonopathy, CSF protein elevate • Sural nerve biopsy: Loss of both myelinated and unmyelinated axons, and small onion bulbs without inflammation. Adrenoleukodystrophy/ Adrenomyeloneuropathy Phenotypic heterogeneity: environmental modifiers, many de novo mutations

Form Frequency Clinical manifestation Adrenoleukodystrophy ~35% Onset: 4-8 YO (ALD) Classic Attention deficit disorder-like behavior changes, rapidly progressing spasticity, visual difficulty, dementia, pseudobulbar palsy, seizures, and adrenal insufficiency. skin hyperpigmentation Adrenomyeloneuropathy 40-50% Onset: 20-30 YO (AMN) adrenal dysfunction; pigmentation, nausea, vomiting, weakness, and hypotensive slowly progressive spastic paraparesis, peripheral neuropathy, and sexual dysfunction Brain MRI: normal, 20%: cerebral demyelination NCS: demyelinating neuropathy, mixed axonal and demyelinating or predominantly axonal changes. Heterozygous females 50% Middle age and a milder degree than males. Progressive spastic paraparesis and sphincter dysfunction NCS (~70 %): mixed multifocal demyelination and axon loss Adrenoleukodystrophy/ Adrenomyeloneuropathy

Treatment Preventive treatment: diet plus Lorenzo’s oil (a mixture of oleic acid and erucic acid) Symptomatic treatment • Early dietary adjustment: Restriction of VLCFAs and saturated fats. • 5-10 mg/day of C26:0, 15% of total calories. • Adrenal hormone replacement: adrenal insufficiency • Hematopoietic stem cell transplantation: • Early stages of classic ALD; 5-year survival rate of 56 % Globoid-Cell Leukodystrophy (Krabbe’s Disease)

• An AR, a deficiency of galactocerebrosidase- b –galactosidase • Accumulation of psychosine and galactocerebroside in oligodendrocytes and Schwann cells. Onset: late-infantile, juvenile, and adult-onset • intellectual regression, visual dif fi culty, and spastic paraparesis but with variable peripheral neuropathic features. Neuropathy: demyelination, and variable axon loss. NCS: motor NCV consistent with an inherited demyelinating neuropathy MRI: WM lesion, calcification Diagnosis: assay of GALC activity in leukocytes, serum, or cultured fibroblasts Tangier Disease

• Mutations in the ABCA1 gene, impaired removal of cellular cholesterol (↓HDL and ↓apolipoprotein A) cholesterol deposition in Schwann cells Clinical: • Cholesterol deposition and include enlarged yellow-orange tonsils, xanthomas, corneal clouding, hepatosplenomegaly,lymphadenopathy, and coronary and carotid artery disease. Neuropathy: Hand or face weakness and numbness (syringomyelia-like pattern), pain is uncommon, symmetric or multifocal pattern, A relapsing- remitting. NCS: no SNAP, Motor nerve conduction are often markedly slow, with prolonged distal motor latencies and occasional conduction block. Tangier Disease

Nerve conduction study • no SNAP, Motor nerve conduction are often markedly slow, with prolonged distal motor latencies and occasional conduction block. Nerve pathology: • Loss of small myelinated and unmyelinated axons • Prominent lipid vacuoles in Schwann cells but not in neurons (paranodal dysfunction) • Demyelination and remyelination. Investigation: • ↓ HDL (<5 mg/dL) and cholesterol (usually <150 mg/dL, but may be normal) levels and increased triglyceride (>300 mg/dL) levels. • Reduced HDL levels in family members • Genetic analysis Treatment: dietary management of lipids Bassen-Kornzweig Disease (Abetalipoproteinemia)

• AR, mutation in the microsomal triglyceride transport protein (MTP). • Pathophysiology; impaired absorption of fat and fat-soluble vitamins through the mucosa of the small intestine. • Lipid profile: ↓chylomicrons, cholesterol, and triglycerides but normal HDL  Vitamin E deficiency Clinical: the fat malabsorption syndrome: progressive ataxia and acanthocytes Neuropathy: axonal sensorimotor neuropathy Treatment: high-dose vitamins E, A, and K. Dietary restriction of very long-chain fatty acids. Fabry’s disease (a-galactosidase deficiency)

• Lysosomal storage disorder caused by mutations in the a - galactosidase-A ( GLA ) gene on chromosome Xq22. • Pathogenesis: deposition of glycosphingolipids in cells throughout the body (vascular endothelial and perineurial cells)

genereviews.org P.K. Richardson and S.T. Demarest Fabry’s disease (α-galactosidase deficiency) Neuropathy: • Small fiber neuropathy: intense burning pain in the distal arms and legs. • Hypohidrosis Pathology: lipid in multiple organs; arterial endothelium, vascular smooth muscle, cardiac muscle, skin, and variably in neurons, muscle Diagnosis: • Deficiency of GLA activity in plasma or leukocytes • GLA mutations Treatment: • Enzyme replacement therapy: agalsidase β and α: ↑ neuropathic pain, cardiac and renal function • Neuropathic pain: Gabapentin, carbamazepine, and phenytoin • Hypertension: ACE inhibitor or ARB Phytanic acid storage diseases (Refsum disease)

• AR, peroxisomal enzyme PHYH or PEX7 gene mutation  prevents adequate fatty acid catabolism via β -oxidation Pathology: accumulation of phytanic acid in serum and tissue. The clinical triad: • Retinitis pigmentosa • Peripheral neuropathy: • A sensorimotor demyelinating polyneuropathy, autonomic neuropathy, nerve hypertrophy in the brachial and lumbosacral plexus. • Pathology: Segmental demyelination, depletion of myelinated fibers, and onion bulbs • Cerebellar ataxia plus a raised cerebrospinal fluid protein. Others clinical: sensorineural deafness, anosmia, ichthyosis, skeletal deformities, and cardiac abnormalities. Treatment: restrict phytanic acid: avoid green vegetables (source of phytanic acid) and animal fat (phytol). Plasma exchange or extracorporeal lipid apheresis: acute situations1

1Kohlschutter A, J Child Neurol. 2011;27(5):654–6. Cerebrotendinous xanthomatosis (cholestanolosis)

• AR, mutation in CYP27A1 gene; a defect in sterol 27-hydroxylase. • Impaired bile acid synthesis with accumulation of cholestanol in tissues. Clinical: • neuropsychiatric symptoms, dementia, pseudobulbar palsy, ataxic or spastic gait, and a mild distal peripheral neuropathy. Neuropathy: primarily an axonopathy, mild demyelination Diagnosis: a high plasma cholestanol with normal cholesterol or genetic analysis. Treatment: oral chenodeoxycholic acid

Meiner V, et.al , Neurology. 1994; 44:288–90. William Connor, MD Diagnostic approach to metabolic causes of peripheral nervous system

Diseases Demyelinating Axonal Motor SFN DRG Acute Multiple neuron mononeuro pathy Energy metabolism disorders

Respiratory chain disorders + +

MNGIE +

PDH deficiency + +

Vitamin E deficiency + + β-Oxidation defects (LCHAD, TFP) + + Biotinidase deficiency + +

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Diagnostic approach to metabolic causes of peripheral nervous system

Diseases Demyelinating Axonal Motor SFN DRG Acute Multiple neuron mononeuro pathy Lipid storage/oligosaccharidoses Cerebrotendinous xanthomatosis + +

GM2 gangliosidosis + +

Fabry disease + Metachromatic leukodystrophy +

Krabbe disease + +

Adrenoleukodystrophy/adrenomyeloneuropathy + +

Refsum disease + + + Peroxisome biogenesis defects + + Diagnostic approach to metabolic causes of peripheral nervous system

Diseases Demyelinating Axonal Motor SFN DRG Acute Multiple neurone mononeuro pathy Lipid storage/oligosaccharidoses Tangier disease + + +

β-Mannosidosis +

Serine palmitoyltransferase mutations (HSAN1) + + + Others Serine deficiency +

Homocysteine remethylation defect + + + Acute intermittent porphyrias + + + + Tyrosinaemia type 1 +

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Myopathy manifestation in neurometabolic disorder Physiology of Energy Metabolism in Muscle Clinical manifestation

• Static disorder: Fixed weakness + others associated symptom e.g. cardiomyopathy, endocrinopathy, encephalopathy. • Dynamic disorder: related to exercise (cramps, myalgias, exercise intolerance, myoglobinuria). • Symptoms suspected metabolic myopathy: exercise induced muscle symptoms, static or progressive myopathy, isolated neuromuscular respiratory weakness, and muscle disease associated with systemic conditions. METABOLIC MYOPATHIES

• Glycogen storage disease • Lipid storage myopathy • Mitochondrial myopathy Amino acid : neurocognitive, no myopathy. Adenylate deaminase def: homozygous 2%, no evidence deficient of cellular energy. Glycolysis and glucogenolysis

Glycogenolysis is the breakdown of glycogen (n) to glucose-6-phosphate. Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate. Clinical manifestation • Onset 2nd or 3dr decade of life. • Symptoms usually begin shortly after exercise initiation with muscle pain and eventually a muscle contracture (muscle contraction in the absence of electrical activity) • Delayed-onset muscle soreness: after exercise. • Rhabdomyolysis or myoglobinuria. Clinical similar among type of GSD except some clinical features.

Ronan J. Walsh, continuum Glycogen storage disorders affecting muscle

Adler, Shieh, Semin Neurol 2015;35:385–397. Investigations • Serum creatine kinase (CK) is chronically elevated in McArdle disease; otherwise it is usually normal in the other glycogen-storage diseases. • Serum uric acid is elevated in 50% • Forearm exercise test shows no lactate with high ammonia rise • Graded exercise stress test: • Second wind phenomenon is seen in McArdle disease • No second wind phenomenon suggests the glycolytic defects • EMG is often normal in cases of glycogen-storage disease • Muscle biopsy may show high glycogen, absent phosphorylase, or absent phosphofructokinase • Genetic testing options • Specific mutation analysis: (R49X in 70% of white individuals with McArdle disease) • Next-generation sequencing panels for glycogen-storage diseases or myopathy panels with glycogen-storage disease genes or whole-exome sequencing

Continuum (Minneap Minn) 2016;22(6):1829–1851 Disorders of Glycolysis/ Glycogenolysis

Diagnosis • (Non)forearm exercise test: Normally, lactate and ammonia rise approximately threefold. • Normal non ischemic forearm test: R/O GSD except Phosphorylase b kinase and Acid maltase deficiency.

Forearm ischemic test Ammonia Lactate Pyruvate

Normal 3-4 times 3-4 times 3-5 times

Glycolysis/glycogenolysis 3-4 times No rise or <2 times No rise or <2 times

Suboptimal effort/ No rise No rise No rise AMPD1 polymorphism Treatment

• Careful and progressive exercise training • Pre-exercise sucrose/glucose in glycogenolytic defects (eg, McArdle disease) • Overnight fasting for glycolytic defects (eg, phosphofructokinase deficiency or Tarui disease) • Creatine monohydrate (0.1 g/kg/d), NOT higher dose • Consider pyridoxine 50 mg/d in patients with null phosphorylase mutations (eg, R49X mutations)

Continuum (Minneap Minn) 2016;22(6):1829–1851 Fatty acid oxidation defect

According to the number of carbons into: Short-chain (2 to 4), Medium-chain (6 to 12), long-chain (14 to 18), very long-chain (20 or more) The oxidation of long-chain and very long-chain free fatty acids requires the carnitine palmitoyltransferase system. Mitochondrial biochemical pathways

AnibhM. Das, Journal of Biomedicine and Biotechnology Volume 2010, Clinical presentation in LSM.

• Exercise-induced myalgia. • Exercise-induced rhabdomyolysis • Recurrent rhabdomyolysis within 24 hours after exercise. • Delayed-onset muscle soreness. • Precipitated by prolonged fasting, prolonged exercise, or superimposed illness. • Fixed proximal muscle weakness: accumulated lipid droplet in muscle Most common LSD

• Carnitine palmitoyltransferase II deficiency • Trifunctional protein deficiency • Very long-chain acyl-CoA dehydrogenase deficiency. • Medium-chain acyl-CoA dehydrogenase deficiency, • Carnitine acylcarnitine translocase deficiency • LPIN1 deficiency Diagnostic testing

• Inter-episode: usually lab. Normal. • NCS and EMG usually normal (If no fix weakness) but sometime found axonal neuropathy (e.g. long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency). • During episode: high CK, hyperkalemia and hypoketotic hypogly-cemia. • The most sensitive and specific test for a fatty acid oxidation defect is the acylcarnitine profile performed by liquid chromatography tandem mass spectrometry. • Total and free carnitine levels may be secondarily abnormal but very low in systemic carnitine deficiency. Summary disorder of lipid metabolism

P. Laforêt, C. Vianey-Saban / Neuromuscular Disorders 20 (2010) Role of muscle biopsy

• Typical exercise intolerant with/without weakness: not required MPX. • Muscle pathology: a nonspecific increase in neutral lipid. • Marked increased lipid droplet in primary carnithine deficientcy (PCD), Multiple acyl-Co A dehydrogenase (MAD) deficiency, Neutral lipid storage disease (NLSD). • Benefit in suspected out mitochondrial myopathy (tissue specific, ETC, RRFs, COX, EM). Muscle pathology in suspected LSM Treatment

• Careful and progressive exercise training; no exercise during illness • Avoid fasting • L-carnitine (only if low or in SLC22A5 mutation transporter defect(PCD) start at 330 mg 2 times per day • Riboflavin 100-400mg/day in MADD or glutaric acidemia type 2 (especially ETFDH mutation) • High-carbohydrate diet especially immediately before and during long-term endurance exercise, and a relatively low-fat (less than 30%) • Carbohydrate before and during exercise • Consider triheptanoin

Wen-Chen Liang, Curr Neurol Neurosci Rep (2011) 11:97–103 Mitochondrial Myopathies

• Defect in electron transport chain function. • A decrease in aerobic energy production from fat and carbohydrate. • As the final common pathway for fat and carbohydrate oxidation. • The disease often occur from tissues with a high metabolic demand such as heart, brain, skeletal muscle, and nerves (especially cranial nerves II and VIII). • Mitochondrial myopathy: skeletal muscle is the pre-dominant tissue involved. o exercise intolerance with or without rhabdomyolysis. Clinical presentation

The extreme phenotypic and genotypic heterogeneity. Mitochondrial myopathy (muscle predominant) • Exercise intolerance • Shortness of breath and premature fatigue during exertion • Exertional nausea and vomiting. • Exacerbated with superimposed infection or fasting. • Uncommon rhabdomyolysis and pigmenturia; cytochrome b, cytochrome c oxidase, and MELAS m.3260A9G mutations. • Limitations in exercise capacity because of a low VO2max. Clinical features of mitochondrial disease in adults.

EMBO Molecular Medicine Vol 7 | No 12 | 2015 Treatment

• Careful and progressive exercise training; no exercise during illness • Avoid fasting • Cocktail treatment consists of coenzyme Q10 or idebenone (5-15 mg/kg/d) plus α-lipoic acid (5-15 mg/kg/d) plus vitamin E (5-15 IU/kg/d) plus creatine monohydrate (0.1 g/kg/d) • L-carnitine, only if levels are low; start at 330 mg 2 times per day and retest Diagnostic approach to metabolic causes of myopathies Diseases Permanent weakness Exercise intolerance and/ Cardiomyopathy or myglobinuria Glycogen storage disorders McArdle disease (GSD-V) + Pompe disease (GSD-II) + + Debranching enzyme (GSD-III) + Branching enzyme (GSD-IV) + Glycolysis defects + + Respiratory chain disorders MELAS + + + MERRF + + + MNGIE (demyeline) + PEO-Kearns Sayre + + + POLG mutations (AHC) + Cytochrome B deficiency +

J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Diagnostic approach to metabolic causes of myopathies Diseases Permanent weakness Exercise intolerance and/ Cardiomyopathy or myglobinuria Fatty acid oxidation defects VLCAD deficiency + + ETF and ETFDH deficiencies + + TFP deficiency + CPT2 deficiency + Primary carnitine deficiency + +

Lipin 1 deficiency (LPIN1) + PNPLA2 mutations (neutral + + lipid storage disorder) CHKB mutations + + Others AGAT deficiency + GAMT deficiency + AMACR deficiency + J.-M. Saudubray et al. (Eds.), Inborn Metabolic Diseases Summary (1) • A complex, heterogenous group of disorders and multi systems diseases • Presentation: acute metabolic decompensate, relapsing-remitting mimic common neuromuscular disorder • Triggered by fasting, exercise, fever, catabolic circumstances or post partum • Neuromuscular presentation found in category of disorders of Energy Metabolism, disorders of Lipid Metabolism and intoxication Syndromes Summary (2)

• Neuropathy can manifestation with mononeuropathy, multiple mononeuropathy, polyaxonopathy, demyelinating poly neuropathy or mixed polyneuropathy, SFN, DRG or motor neuronopathy. • Muscular manifestation can preset with exercise intolerance, rhabdomyolysis, progressive proximal muscle weakness. • Management usually symptomatic, enzyme replacement therapy in some disease, Bone marrow transplantation, dietary change and avoid trigger or metabolic decompensation. Thank you for your attention