LPIN1 – muscle - specifi c phosphatidic acid phosphatase a
Biochemical abnormality incompletely characterized
Impaired long - chain fatty acid oxidation a Impaired function of the sarcoplasmic
reticulum in familial malignant hyperthermia (predisposition in central core disease) a
Abnormal composition of the sarcolemma in, for example, Duchenne and Becker muscular dystrophy a
Biochemical abnormality unknown Familial recurrent myoglobinuira a Repeated attacks in sporadic cases a
Modifi ed from Tein I, DiMauro S, Rowland LP.
Myoglobinuria. In: Rowland LP, DiMauro S (eds), Handbook of Clinical Neurology , vol 18.
Myopathies . Amsterdam: Elsevier Science Publishers BV, 1992.
a Etiologies that have been documented to cause recurrent myoglobinuria beginning in childhood.
recessive, autosomal dominant, X - linked, spo- radic, or inherited by maternal mitochondrial transmission.
In FAO disorders, attacks of myoglobinuria are precipitated after mild - to - moderate prolonged exercise when fatty acids are the key energy source in exercising muscle. These attacks may be further exacerbated by inadequate caloric intake as in fasting or infection with vomiting, which further limit blood glucose. Other risk factors include infection, during which meta- bolic processes preferentially favor FAO; this per- sists despite glucose administration, thereby increasing the dependence on FAO. There may also be fever with shivering thermogenesis and vomiting with fasting, making this a common trigger. Cold exposure may be detrimental as shivering depends upon involuntary muscle activity which primarily depends upon long - chain fatty acids (LCFAs). Emotional stress has also been a recognized precipitant. Other possi- ble mechanisms relate to the toxicity of elevated FFAs arising proximal to the block, especially LCFAs which may be membranotoxic.
Myoadenylate deaminase and glucose - 6 - phosphate dehydrogenase (G6PD) defi ciencies have not been conclusively linked to causation because both enzymes may be absent in asymp- tomatic people.
There appear to be differences in the distribu- tion of etiologies of heritable myoglobinuria in adults versus children. In a study of 100 cases of recurrent childhood - onset myoglobinuria, only
tips and tricks for performing forearm ischemic exercise test After 1 min of repetitive maximal grip exercise under ischemic conditions, blood samples from the antecubital vein are sequentially obtained at 1, 3, 5, 7, 10, and 15 min. In healthy individuals there is a four - to sixfold increase of lactate over baseline, with the peak occurring at 1 – 2 min after exercise, which declines to baseline values by 15 min. This is paralleled by a similar fi vefold or more increase in ammonia, with levels generally peaking at 2 – 5 min after exercise in individuals with normal myoadenylate deaminase activity. In individuals with a defect in glycolysis/
glycogenolysis, there is an insuffi cient rise in lactate (less than twofold), with a
compensatory and exaggerated increase in ammonia, which also indicates suffi cient effort on the part of the individual. An insuffi cient lactate rise has been demonstrated in PPL, debrancher, PFK, phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), and lactate dehydrogenase (LDH) defi ciencies but not in acid maltase or phosphorylase b kinase defi ciency. The major limitation of this test is that the rise of venous lactate in individuals who do not have a defect in this pathway is highly dependent on the patient ’ s ability and willingness to exercise.
Therefore patients in whom lactate levels are low due to poor effort, or to placement of the venous line in other than the median cubital vein, show proportionally blunted ammonia responses. The test should be immediately truncated if the patient develops an acute cramp, because myonecrosis may occur in an individual with a glycolytic disorder.
24% of children were diagnosed biochemically – 16 with carnitine palmitoyltransferase (CPT) II defi ciency and 7 with various glycolytic/glycog- enolytic defects. These children were divided into two groups: a type I exertional group with exer- tion as the primary precipitating factor and a type II toxic group with infection and/or fever and leukocytosis as the primary precipitants. The type II toxic childhood group was distinguished from the type I exertional childhood - and adult - onset groups by its etiologies, which were limited to FAO defects and slight female predominance in contrast to the marked male predominance in the latter two groups. The type II toxic group was further distinguished by its earlier age at onset of attacks of myoglobinuria, the presence of more generalized disease (e.g. ictal bulbar signs, encephalopathy, seizures, developmental delay), and a higher mortality rate. In a study of 77 adult patients, Tonin et al. identifi ed the enzyme abnormality in 36 patients: CPT II defi ciency in 17 patients; glycolytic/glycogenolytic defects in 15 patients; and combined CPT II and myoade- nylate deaminase in one individual. The most common etiology overall for recurrent myoglob- inuria in children, boys and girls, is CPT II defi - ciency and in adults is phosphorylase defi ciency followed by CPT II defi ciency. Differentiation of classic CPT II from phosphorylase defi ciency is given in Table 5.2 .
Glycolytic/ g lycogenolytic d isorders The clinical features, affected tissues, and enzyme defects of the muscle glycogenoses are shown in Table 5.3 . Glycogen accumulation in muscle may or may not be present. Phosphorylase defi ciency or McArdle ’ s disease is the most common glycog- enosis resulting in recurrent myoglobinuria.
Certain defects such as phosphorylase (PPL) and phosphofructokinase (PFK) defi ciencies can be detected on muscle histochemical staining.
Individuals with defective glycolysis/glycoge- nolysis are most vulnerable during the initial stages of intense exercise, and they must rest soon after starting exercise because of muscle cramps. However, if they continue to exercise at low intensity for 10 – 12 min, they are then able to continue for a longer time. This is known as the second - wind phenomenon and has been attrib- uted to a metabolic switch from carbohydrate to fatty acid utilization and to increased circulation,
with increased availability of blood glucose from hepatic glycogenolysis.
The forearm ischemic exercise test is a useful test for the detection of enzymatic defects in the non- lysosomal glycogenolytic and glycolytic pathways.
Table 5.2. Differentiation between disorders of glycogen versus lipid metabolism resulting in exercise intolerance and/or myoglobinuria
Glycolytic/Glycogenolytic Fatty acid oxidation
Phosphorylase defi ciency Carnitine palmitoyltransferase II defi ciency “ adult type ”
Symptom onset in exercise Early (fi rst few minutes) Late (particularly after 1 hour)
Second wind + –
Myalgia Cramps Stiffness
Fixed weakness More common Less common
Elevated interictal creatine kinase
+ −
Abnormal forearm + −
ischemic lactate test
Delayed ketogenesis − +
Muscle biopsy ± glycogen storage ± lipid storage
Taken with permission from Tein I. Approach to muscle cramps, exercise intolerance and recurrent myoglobinuria. Proceedings of the 38th Annual Meeting of the Canadian Congress of
Neurosciences. Muscle Diseases Course, Quebec City, Canada, 2003: 1 – 29 (CME course).
Treatment in PPL defi ciency includes the administration of glucose or sucrose and Vitamin B6. However glucose is ineffective in PFK and more distal glycolytic disorders. Acid maltase defi ciency (AMD) may present with three very different clinical presentations including: (1) severe generalized disease of infancy described by Pompe, which is fatal before age 2 years and involves diffuse infantile hypotonia, macroglos- sia, respiratory weakness, cardiomyopathy, myopathy, hepatomegaly, and anterior horn cell disease; (2) a juvenile variant affecting exclu- sively muscle with onset in childhood and death by the second or third decade; and (3) a milder, adult - onset variant simulating limb – girdle myopathy. Enzyme replacement therapy appears promising in childhood and late - onset AMD. A high protein diet has been advocated for PPL, phosphorylase b kinase, and PFK defi ciencies.
Fatty a cid o xidation d isorders
Defects in FAO are an important group of disor- ders because they are potentially rapidly fatal and a source of major morbidity encompassing a spectrum of clinical disorders, including recur- rent myoglobinuria, progressive lipid storage myopathy, neuropathy, pigmentary retinopathy,
progressive cardiomyopathy, recurrent hypoglyc- emic hypoketotic encephalopathy or Reye - like syndrome, seizures, and cognitive delays ( Table 5.4 ). There is frequently a family history of sudden unexpected death syndrome (SIDS) in siblings as these are all autosomal recessive dis- orders. Early recognition and prompt institution of therapy and appropriate preventive measures, and in certain cases specifi c therapy, may be life saving and signifi cantly decrease long - term morbidity, particularly with respect to central nervous system sequelae. There are at least 21 recognized enzyme defects in FAO. Newborn screening of blood spot acylcarnitines has been instituted in a number of countries and has con- tributed to the early detection of these disorders.
The most common defect is medium - chain acyl - CoA dehydrogenase (MCAD) defi ciency with an incidence as high as 1 in 8930 live births in the Pennsylvania newborn screening program. There are differentiating biochemical profi les of the FAO disorders. The clinical picture, in combina- tion with an analysis of serum acylcarnitines, urinary organic acid profi les, and urinary acylg- lycines, may suggest a specifi c site of defect and the chain - length specifi city of the defect (e.g.
short, medium, or long chain), after which
Table 5.3. Clinical presentation of muscle glycogenoses
Type Enzyme defect Affected tissues Clinical presentation II
Infancy
Acid maltase Generalized Cardiomegaly, weakness, hypotonia, death age < 1 year II
Childhood
Acid maltase Generalized Myopathy simulating Duchenne dystrophy, respiratory insuffi ciency II
Adult
Acid maltase Generalized Myopathy simulating limb girdle dystrophy or polymyositis, respiratory insuffi ciency
III Debrancher Generalized Hepatomegaly, fasting
hypoglycemia, progressive weakness
IV Brancher Generalized Hepatosplenomegaly, cirrhosis
of liver, hepatic failure, myopathy, cardiomyopathy, APBD
V Muscle
phosphorylase
Skeletal muscle Intolerance to intense exercise, cramps, myoglobinuria VII Muscle
phosphofructokinase
Skeletal muscle RBCs
Intolerance to intense exercise, cramps, myoglobinuria VIII Phosphorylase kinase Liver Asymptomatic hepatomegaly VIII Phosphorylase kinase Liver and
muscle
Hepatomegaly, growth retardation, hypotonia VIII Phosphorylase kinase Skeletal muscle Exercise intolerance,
myoglobinuria
VIII Phosphorylase kinase Heart Fatal infantile cardiomyopathy IX Phosphoglycerate
kinase
Generalized Hemolytic anemia, seizures, learning disability, intolerance to intense exercise,
myoglobinuria
X Muscle
phosphoglycerate mutase
Skeletal muscle Intolerance to intense exercise, myoglobinuria
XI Muscle lactate dehydrogenase
Skeletal muscle Intolerance to intense exercise, myoglobinuria
XII Aldolase A Skeletal muscle
RBCs
Nonspherocytic hemolytic anemia, exercise intolerance, weakness
XIII β - Enolase Skeletal muscle Exercise intolerance Modifi ed from DiMauro S, Lamperti C. Muscle glycogenoses. Muscle Nerve 2001; 24 :985.
APBD, adult polyglucosan body disease; RBCs, red blood cells.
Modifi ed from Tein I. Fatty acid oxidation and associated defects. American Academy of Neurology Proceedings . Seattle. Madison, WI: Omnipress, 1995.
Table 5.4. Clinical features associated with specifi c genetic defects of fatty acid oxidation Defi ciency Fasting disorder Tissue involved Hypoketotic hypoglycemia Altered carnitine Dicarboxylic acids Reye - like syndrome SIDS LCFAUD + L + + NR NR NR OCTN2 + H, M + + NR + NR CPT I + K + + NR + NR TRANS + H, M, (Mg) + + NR + + CPT II (mild) ± M, Mg, P NR + NR NR NR CPT II (severe) + H, M, Mg, L + + NR + + VLCAD/LCAD + H, M, Mg, L + + + + + ACAD9 + B, H, L, M, Mg + + + + NR Trifunctional/LCHAD + H, M, Mg, L, N, P, R + + + + + Dienoyl - CoA reductase NR M, D, B, (H) NR + NR NR NR MCAD + (Mg) + + + + + SCAD + M, B, D, H ± + + NR + SCHAD + H, M, Mg, L + + + NR + ETF and ETF/Qo + M, H, K, B, D + + + NR + HMG - CoA lyase + B, P + + + + + ? ACAD9, acyl - CoA dehydrogenase 9; B, brain; CPT, carnitine palmitoyltransferase; D, dysmorphic features; ETF, electron transfer fl avoprotein; H, heart; HMG, β - hydroxy - β - methylglutaryl; K, kidney; L, liver; LCAD, long - chain acyl - CoA dehydrogenase; LCFAUD, long - chain fatty acid uptake defect; M, muscle; MCAD, medium - chain acyl - CoA dehydrogenase; Mg, myoglobinuria; N, neuropathy; NR, no case yet reported; OCTN2, plasmalemmal high - affi nity carnitine transporter; P, pancreatitis; Qo, coenzyme Q oxidoreductase; R, retinopathy; SCAD, short - chain acyl - CoA dehydrogenase; SCHAD, short - chain l - 3 - hydroxyacyl - CoA dehydrogenase; TRANS, carnitine acylcarnitine translocase; trifunctional, long - chain enoyl - CoA hydratase + long - chain l - 3 - hydroxyacyl - CoA dehydrogenase + long - chain 3 - ketoacyl - CoA thiolase; VLCAD, very - long - chain acyl - CoA dehydrogenase.
mal carnitine transporter (OCTN2) defect, of questionable value in short - and medium - chain FAO defects, and potentially deleterious in long - chain FAO disorders.
Mitochondrial d isorders
The prevalence of mtDNA point mutations that cause disease is estimated as 1/5000 to 1/10 000 and the frequency of mtDNA mutations among healthy individuals as 1/200. This suggests that mitochondrial diseases are among the most common metabolic disorders. POLG mutations are a major cause of human disease, possibly accounting for up to 25% of all patients with mitochondrial disease, with a variety of clinical syndromes, in which the autosomal recessive mutations tend to cause mtDNA depletion and present in childhood, whereas the dominant mutations tend to cause adult - onset disease with multiple secondary deletions of mtDNA.
Mitochondrial diseases are clinically heteroge- neous. There may be variation in the age at onset, course, and distribution of weakness in pure myopathies. On average, the age of onset refl ects the level of mutation and the severity of the biochemical defect; however, other factors includ- ing nuclear genetic and/or environmental factors can also affect the expression of disease.
Additional features may include exercise intoler- ance and premature fatigue. The most common presenting clinical features include short stature, sensorineural hearing loss, migraine headaches, ophthalmoparesis, myopathy, axonal neuropa- thy, diabetes mellitus, hypertrophic cardiomy- opathy, and renal tubular acidosis. Additional features may include stroke - like episodes, sei- zures, myoclonus, retinitis pigmentosa, optic atrophy, ataxia, gastrointestinal pseudo - obstruction, and hypoparathyroidism. Inheri- tance may be autosomal recessive which accounts for most cases, autosomal dominant, X - linked, or maternal mtDNA transmission (Box 5.2 ). In the case of mtDNA mutations, the expres- sion of the phenotype depends upon the ratio of mutant to wild - type mtDNA in a given tissue and the tissues involved.
The diagnosis of mtDNA - related disorders requires a careful synthesis of the clinical history, signs, mode of inheritance with detailed family pedigree, laboratory data (serum lactate and specifi c enzyme assays in fi broblasts and
molecular mutation analysis may be done to confi rm the specifi c gene defect and screen family members.
General treatment approaches include the strict avoidance of precipitating factors such as prolonged fasting, prolonged aerobic exercise ( > 30 min), and cold exposure leading to shivering thermogenesis. A high carbohydrate load before exercise is advisable with a rest period and repeat carbohydrate load at 15 min. In the event of pro- gressive lethargy, obtundation, or poor oral intake because of vomiting, urgent intravenous glucose therapy is indicated (8 – 10 mg/kg per min glucose infusion). In general, it is advisable to institute a high - carbohydrate, low - fat diet with frequent feedings throughout the day, particu- larly a bedtime snack, commensurate with the nutritional needs of the child given his or her age with the aid of a metabolic dietician. Augmen- tation of the diet with essential fatty acids (at 1 – 2% of total energy intake) is often used to reduce the risk of essential fatty acid defi ciency.
Flaxseed, canola, walnut, or saffl ower oils can be used for this purpose. To delay the onset of fasting overnight in children who manifest symptoms of early morning hypoglycemia, the nightly institu- tion of uncooked cornstarch will prolong the postabsorptive state and delay fasting. Cornstarch provides a sustained - release source of glucose, thereby preventing hypoglycemia and lipolysis, but may result in undesirable weight gain.
Specifi c measures include ribofl avin substitu- tion in certain cases of multiple acyl - CoA dehydrogenase defi ciencies, medium - chain trig- lyceride (MCT) oil in long - chain FAO disorders, and oral prednisone and docosahexaenoic acid (essential polyunsaturated fatty acid or PUFA) in myoneuropathic long - chain 3 - hydroxyacyl - coenzyme A dehydrogenase (LCHAD) defi ciency.
Bezafi brate, a peroxisome proliferator - activated receptor (PPAR) agonist, increases long - chain FAO in defi cient fi broblasts and is being consid- ered as a future mode of therapy, although indi- viduals should be monitored for possible drug - induced increase in serum CK because there have been rare reports of myoglobinuria in patients with renal insuffi ciency who tend to accumulate the drug. Carnitine therapy is abso- lutely essential in the high - affi nity plasmalem-
Box 5.2. Genetic classifi cation of mitochondrial respiratory chain diseases
Defects of mitochondrial DNA
1. Mutations in mitochondrial protein