Approach of metabolic myopathy

Adult-onset treatable myopathy
0 EI + – GYS1 19q13.33 Glycogen synthase-M Cytoplasm
0 EI + – GYG1 3q24 Glycogenin Cytoplasm
II FW + + GAA 17q25.3 Acid-α-glucosidase Lysosome
III FW – + DBR1 3q22.3 Debrancher Cytoplasm
IV FW – + GBE1 3p12.2 Brancher Cytoplasm
V EI – + PYGM 11q13.1 Myophosphorylase Cytoplasm
VII EI – + RBC PFKM 12q13.11 Phsophofructokinase-M Cytoplasm
VIII EI + – PHKA PHKB
X EI – – RBC PGAM2 7p13 Phosphoglycerate mutase-M Cytoplasm
XI EI – – LDHA 11p15.1 Lactate dehydrogenase-M Cytoplasm
XII EI – – ALDOA 16p11.2 Aldolase A Cytoplasm
XIII EI – – ENO3 17p13.2 β-Enolase Cytoplasm
XIV EI – – PGM1 1p31.3 Phosphoglucomutase Cytoplasm
Muscle glycogenosis
Pompe disease (GSD II)
=> Defect of glycogenolysis
* acid maltase
The GAA gene:
• On chromosome 17q25
• Common mutations in different ethnic groups:
- Caucasian: c.-32-13T>G splicing mutation
- African: p.R854X
• Common sequence variation cause pseudodeficiency: p.G576S in Taiwanese and Japanese
Clinical phenotype of Pompe diseae
• Infantile-onset Pompe disease (IOPD)
- GAA activity: typically <1% of normal mean
• Late-/Later-onset Pompe disease (LOPD: including childhood- onset and adult-onset)
- Heterogeneous clinical manifestations
- respiratory insufficiency could occur early
- cardiac involvement is rare
Enzyme replacement therapy (ERT)
- In IOPD: prolonged the survival and ventilator-free period; rescued the cardiomyopathy
- In LOPD: improved the weakness and lung function to different extent
=> ERT is more effective at addressing cardiomyopathy
• CRIM (cross-reactive immunologic material)-negative patients showed poorer outcomes to the ERT
• Earlier treatment seems to lead to better outcome
Treatment of glycogenosis except for GSDII
• Still no ERT
• Dietary intervention (carbohydrate-rich??)
- Most common
(also known as glutaric aciduria type II, GA II)
- Primary carnitine deficiency
Constant or progressive muscle weakness
with/without episodic metabolic decompensation
(low intensity > 10 minutes)
Increased all-length-chain acylcarnitines
PCD
MADD
Nonspecific or uncategorized metabolic profile
Specific metabolic profile for different chain-length FAO defects
Mutation analyses for target genes
Re-evaluation
Re-evaluate the patient. If lipid dysmetabolism is still preferred, go
to mutation analysis directly.
Lipin-1 deficiency
Re-evaluate the patient. If lipid dysmetabolism is still preferred, go to mutation
analysis directly.
Specific metabolic profile for different chain-length
FAO defects
Re-evaluation
VLCAD deficiency Control
• IHC (VLCAD)
• Enzymatic activity
Treatment of CPTII/VLCAD deficiency
• Clinical (late-onset): episodic rhabdomyolysis + often respiratory failure => later retinopathy and peripheral neuropathy
• Pathological: could be mild lipid accumulation then neuropathic change
• Metabolic (MS/MS): elevated long-chain acylcarnitines
• Genetic: HADHA or HADHB
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Age (Y)
Muscle weakness
Respiratory failure
Rhabdo- myolysis
Muscle pathology
Polymyositis, suspected
Elevated C16-OH acylcarnitine
No significant change
> Preceding event of muscle symptoms: usually infection or fasting > CK: up to 20K ~ 40K IU/L during rhabdomyolysis;
could be normal between each episode of muscle weakness/rhabdomyolysis
Case example of TFP deficiency
Lipid storage myopathy
• Neutral lipid storage disease with ichthyosis (NLSDI)
• Neutral lipid storage disease with myopathy (NLSDM)
• Barth syndrome?
Solute carrier family 22, member 5 (SLC22A5)
*
*
• Infantile
- Reye-syndrome-like
Oil red O
Diagnosis and Treatment
- Muscle pathology: lipid storage
- Mutation analysis of SLC22A5
• β -subunit (ETFB)
• ETF dehydrogenase (ETFDH)
• Hypotonia, hepatomegaly, hypo-ketotic hypoglycemia, hyperammonemia, metabolic acidosis, usually lethal
• Mostly caused by ETFA and ETFB mutations
• Late-onset form (childhood-adult)
• Episodic aggravation of muscle weakness, preceded by infection, fasting or heavy exercise
• Hypoglycemia, hepatomegaly, encephalopathy
Pathological characters of MADD
• All 15 patients with RR-MADD from 11 families had ETFDH
mutations.
1 11y
*
Liang et al. Neuromuscul Disord 2009 No specific haplotype linked to this mutation,
c.250G>A (p.A84T)
p.A84T (c.250G>A)
Blue for FAD-binding domain; Green for ubiquinone-binding domain
Cylinder for alpha-helices; arrow for beta-strands Refer to Zhang et al., PNAS 2006
High resolution melting curve analysis
Er et al., Clinica Chimica Acta 2010
Pat. Mutation
Muscle weak.
5 23y
Carrier rate: 4 in 500 (0.85%)
Diagnosis and treatment of MADD
• Diagnosis • Urinary organic acid, MS/MS (blood carnitine and
acylcarnitines)
• Treatment • Riboflavin (VitB2)
• Carnitine
• CoQ10
MS/MS (mainly for detecting the disorders of amino acid and fatty acid oxidation)
Summary of MADD
• All patients have neck muscle weakness and body weight loss
=> characteristic clinical features in MADD
• Two patients died of metabolic crisis
=> late-onset MADD could be lethal; early
diagnosis and treatment are critical
• All patients harbor p.A84T mutation in ETFDH
=> may be a founder mutation
• The mutations are located in FAD-binding domain
=> may change the protein conformation and
then affect the affinity of FAD to ETF-QO and the
electron transfer in mitochondria
=> A hot spot mutation, c.250G>A (p.A84T) with carrier frequency up to 1% in southern Chinese population !
Neutral lipid storage diseases
Autosomal recessive
Circulation 2002
Autosomal recessive
– NLSDI (CDS) ABHD5 (CGI-58)
TFP deficiency – one of differentiation