Key features on examination \200 \200 Tender red palpable nodules over the anterior shins. Older lesions appear bruised, ulcerati on is rare. Lupus profundus Key features on history \200 Panniculitis is a rare complication of SLE occurring in 1 \200\2233% of patients with SLE. Activity of panniculitis appears not to mirror activity of SLE. CHAPTER 18 Miscellaneous diseases 515 Key features on examination \200 The lesions are tender red-blue subcutaneous nodules, which may ulcerate. Typically they oc cur on face, upper arms thighs, and buttocks. Alpha-1 antitrypsin de \201 ciency Alpha-1 antitrypsin is associated with panniculitis. Hi sto- logically, the appearances are a lobular, septal, or a mixed panniculitis. Post-steroid panniculitis Panniculitis may follow steroid therapy especially in chil- dren. It may recur with reuse of corticosteroids. The pathogenesis is not known. Histiocytic cytophagic panniculitis This is a chronic histiocytic disease of subcutaneous f at, ac- companied with panniculitis, fever, serositis, and lymph a denopathy. The haemophag ocytic syndrome may occur. Prednisolone and immunosuppression may be useful. Lipoatrophic panniculitis Rothmann \200\223Makai syndrome (lipogranulomatosis subcuta- nea) is a form of subcutaneous lipoatrophy that occurs after an in \202 ammatory disease in ch ildren. There are multi- ple erythematous lesions on the extremities which heal with subcut aneous atrophy. Fever may be present. Treat- ment is uncertain. Figure 18.4 MRI Sagittal T1-weighted showing multiple low signal areas indicating osteonecr osis and marrow oedema. In a patients with metastatic pancreatic fat necrosis. Differential diagnosis The differential diagnosis of EN includes other forms of panniculiti s, insect bites (history and evidence of a puncture wound), thrombophlebitis, and celluliti s. Investigation Histologically, there is evidence of both septal and lobular panniculitis. Treatment \200 EN is usually self-limiting, NSAIDs may be needed for arthralgias/myalgias. Chronic relapsi ng forms of panniculitis may respond to corticosteroids or other immunosuppressive drugs. General investigations \200 Infection screen, especially looking for evidence of upper respiratory tract infection, thr oat swab, and ASO titre. Chest radiograph looking for infection (especially Mycobacterial) or bilateral hilar lymphadenopathy sug- gestive of acute sarcoidosis. Appropriate serologic al investigations, biopsy, and cul- tures may be required in areas where Mycobacterial and fungal infections are common. Investigation for in \202 ammatory bowel disease is unneces- sary in asymptomatic patients, as this usually sympto- matic when accompanied by panniculi tis. Autoantibody serology if there is evidence of a connec- tive tissue disorder Amylase a nd lipase should be measured in patients pos- sibly with pancreatic disease. Biopsy if the diagnosis is in doubt. A deep wedge biopsy including subcutaneous fat is necessary References Callen JP. Panniculitis. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC (eds) Oxford Textbook of Rheumatology, 3rd edn. Oxford: 2004: 1031 \200\22335. See also Sarcoidosis SLE ALKAPTONURIA 516 Alkaptonuria De \201 nition A rare autosomal recessive condition resulting from lack of homogentisic ac id oxidase, and the accumulation of homo- gentisic acid causing ochronosis and ochronotic a rthropa- thy. Ochronosis is the characteristic black pigmentation seen in alkpatonuric pati ents. Pigmentation of the auricular cartilage appears as a slate- blue or gray color in the conch a, antihelix, and tragus. General investigations \200 The acute phase response is normal. RF and ANA are negative. HLA-B27 is generally negative. A sample of urine should be left to stand. It will darken if it contains excessive amounts of homogentisic acid. Homogentisic acid levels in plasma and urine may be determined by hi gh-performance liquid chromatography. Alkaptonuria was the \201 rst human condition in which the pattern of Mendelian inheritan ce was recognized by Gar- rod in 1902. Garrod in 1908 hypothesized that a speci \201 c enz yme was lacking. Imaging X-rays On plain radiography of the lumbar spine the characteristic \201 ndings ar e: \200 \200 \200 Epidemiology \200 \200 The highest frequency occurs in Slovakia (1/19 000). The overall frequency is 1/250 000 \200\223 1/million live births. Wafer like calci \201 cation of intervertebral disks. Narrowing of disc spaces. Ossi \201 cation of the of the ligaments. Etiology \200 Alkaptonuria is due to lack of the enzyme homogentisic acid oxidase (HGO). The gene for thi s enzyme is located on 3q21 \200\22323. A variety of different mutations have been describe d including nonsense, missense and frame shift mutations. There does not appear to be any c orrelation between the HGO mutation and severity of disease. Homogentisic acid oxidase cata lyzes the oxidative cleav- age of the ring of homogentisic acid into maleylacetoace- tic ac id. Homogentisic acid then accumulates slowly in the tissues, resulting in the charactersti c black pigmenta- tion. The renal clearance of homogentisic acid is high suggesting active renal tubular excretion. Inheritance as an autosomal recessive condition. The exact mechani sm by which pigment deposition results in arthropathy is not known. In peripheral joints the appearances of osteoarthritis de- velop about 10 years after the s pinal changes. Multiple intra-articular radio-opaque loose bodies may be seen in the knees. Synovial \202 uid Effusions occur in around 50% of patients. The synovial \202 uid is c haracteristically non-in \202 ammatory, containing mainly mononuclear cells (100 \200\2237 00 cells/mm3). Pyrophos- phate and apatite crystals have been found in alkaptonuric patient s. \200 Clinical features Key features on history \200 In infancy, the \201 rst feature may be the mother noticing a dark discolouration of the nappies. In adults there is often a history of dark urine (in half of patients this is the presenting feature) or urine that dark- ens on standing. Musculoskeletal \200 Joint pain often starts before the age of 30 years. Initially, this is spinal and then a pe ripheral arthritis develops. Episodic joint in \202 ammation occurs later. Cutaneous \200 Pigmentation of the sclera and ear is rarely seen before 20 \200\22330 years of age. Adult alkpatonuric patients may have dark urine or urine that darkens on standing. Key features on examination Musculoskeletal \200 \200 Figure 18.5 Lumbar disc calci \201 cation in a patient with longstanding ochronosis. Marked spinal stiffness at all levels with kyphosis. Large joint osteoarthritis is common, particularly knee, hip, and shoulder. Small joint involvement is unusual. They may be a joi nt effusion. Differential diagnosis \200 \200 The main differential diagnosis is from osteoarthritis, ankylosing spondylitis, and calcium pyrophosphate depo- sition disease. Ankylosing spondylitis can be distinguished from ochro - nosis by the presence of syndesmophytes, erosion, and fusion of the sacroiliac joints. Cutaneous \200 Ochronotic pigmentation in the eye is visible at the insertion of the rectus muscles, and m ay spread to the conjunctiva and sclerae. CHAPTER 18 Miscellaneous diseases 517 Resources Patient organizations The Alkaptonuria society. www.alkaptonuria.info Osteophytosis on X-ray is not present in ochronosis, but is a typical feature of osteoarthr itis. Ochronosis affects shoulders and sacroiliac joint, which are less frequently involved in osteoarthritis. Others OMIM: www.ncbi.nlm.nih.gov/entrez/ OMIM 203500 Pathology Biopsies show ochronotic pigment in the cartilage. This is located within collage n bundles causing loss of striation, swelling, and fracture. ICD-10 coding E70.2 Disorders of tyrosine metabolism Patient advice \200 References Phornphutkul C, Introne W, Perry M, et al. Natural history of alkap- Genetic counseling about mode of inheritance. Screening of \201 rst degree relatives. Rar e inherited condition resulting in arthropathy. tonuria. N Engl J Med 2002; 347: 2111 \200\22321. Suwannarat P, O \200\231Brien K, Perry MB, et al. Use of nitisinone in alkap- tonuria. Metabolism 2005; 7: 719 \200\22328. Treatment \200 There is no treatment for the underlying enzymatic defect. Vitamin C has been used, but is not effective. Nitisinone has been used on an experimental basis and reduces urinary HGA le vels. The long-term effect on joint function is unknown. Analgesics, NSAIDs, physiotherapy as required. Joint replacement may be required in severe cases. Lumbar spinal stenosis may require surgical decom- pression. See also Osteoarthritis Spondyloarthropathy \200 \200 GAUCHER \200\231S DISEASE 518 Gaucher \200\231s disease De \201 nition Gaucher \200\231s disease results from accumulation of glucosylce- ramide i n organs in the storage Gaucher cells. Acute pain, tenderness possibly with fever may occur in osteonecrosis. Key features on examination Hematological Hepatosplenomegaly. Three types of Gaucher \200\231s disease are recognized. Types of Gaucher \200\231s disease Type 1 (non-neuronopathic) \200 \200 Musculoskeletal \200 \200 Pain and limitation of movement occur in osteonecrosis. Growth retardation. Organomegaly. Hypersplenism leading to hematological abnormalities. Bone lesions due to med ullary in \201 ltration by Gaucher cells. No CNS involvement. Type 2 Key features on history \200 Early onset of oculomotor abnormalities. Key features on examination Hematological \200 Type 2 (acute neuronopathic) \200 \200 Early CNS involvement. Fatal by age 2 years. Hepatosplenomegaly Neurological \200 Type 3 (subacute neuronopathic) \200 \200 \200 Bilateral \201 xed strabismus and oculomotor apraxia are early signs. Hypertonia neck mus cles and opisthotonus. Organ involvement. Medullary lesions. CNS involvement, but less severe than in type 2. Type 3 Intermediate between types 1 and 3. The neurological features are similar to type 2. Epidemiology Gaucher s disease is an autosomal recessive condition Type 1 is the most commo n and occurs most frequently in Ashkenazi Jew (prevalence 15 \200\22340/100 000), but occur s in all ethnic groups (1/100 000). Can occur at any age, but the median age is 30 years. General investigations \200 \200 Investigation is directed at establishing the diagnosis. FBC anemia, leucopaenia, thrombocy topaenia due to hypersplenism. Cholestatic enzymes may be increased but liver failure is un common. Serum ACE, tartrate resistant acid phosphatase is raised. Leucocyte glucocerebrosid ase is elevated. Type 2 and 3 are much rarer and predominately occur in non-Jewish patients. Type 2 presents age <6months and type 3 age <20 years. Etiology Biochemistry Gaucher \200\231s disease arises from a defect in the gene for glucoc erebrosidase, which results in decreased activity. Glucocerebrosidase is 65 kDa membrane as sociated mon- omeric protein, which hydrolyses B-glucosidic ester bonds. Decreased activity of the enzyme results in accumulation of glucosylceramide linked by a B-glucosidic bond. G luco- sylceramide is the end product of glycosphingolipid catab- olism and is normally degr aded into ceremide and glucose by glucocerebrosidase. Genetic screening Patients with typical clinical features should be screened for the common mutations. Imaging \200 \200 Plain radiographs show typical appearances. Failure of skeletal remodeling leads to develop ment of the \200\230Erlenmeyer \202 ask \200\231 deformity with expansion of the contour s of long bones, there is cortical thinning and loss of the normal concavity. Vertebral bod ies show depres- sion of the superior and inferior endplates \200\230H-vertebra \200\231. Bone marrow in \201 ltration results in osteolytic lesions. Osteonecrosis results in joint damage with appearances identical to idiopathic osteonecrosis. MR is the most sensitive me thod of assessing for assess- ing bone marrow in \201 ltration by Gaucher cells and can be used to assess response to treatment. Molecular genetics The gene for B-glucocerebrosidase is located at 1q21. The most common mu tations are N370S. and L444P. A wide phenotypic difference is seen with some mutations lead ing to a mild phenotype (e.g. R496H), whilst some lead to loss of catalytic activity and en zyme stability (e.g. L444P). \200 Clinical features Type 1 Key features on history There is a broad spectrum of severity, wit h onset at any age. Mental development is normal. Bone marrow biopsy The diagnosis is made on the demonstration of Gaucher cells in bone marr ow biopsy. The cells are large mono- or multinucleated cells with a typical \200\230wrinkl ed tissue paper \200\231 appearance of the cytoplasm. Musculoskeletal \200 Differential diagnosis The diagnosis is based on clinical manifestations and the radiologic al appearances. The plain radiographic appearances Episodic arthralgias. Most frequently involving the spine, hips, legs, and shoulders. Fract ures may occur to bone fragility. CHAPTER 18 Miscellaneous diseases 519 are not speci \201 c for Gaucher \200\231s disease. The diagnosis should be considered in a patient with hepatosplenomegaly, osteopaenia, focal osteosclerosis, osteonecrosis, and Er lenmeyer \202 ask deformities. galy within a few weeks, but the osseous complications take longer to reverse. The optimum treatment regimens for milder type 1 disease is still uncertain. Resources Patient organizations www.gaucher.org.uk Prognosis \200 The prognosis is variable dependent on the precise mutation as there is a very broad clinic al heterogeneity. The more severe forms have a worse prognosis with progressive hyperspleni sm, bone pain, skeletal deformity, and fracture. However, enzyme replacement therapy revers es hypersplenism and bone pain, and reduces fractures. Type 2 is fatal before age 2 years. Others OMIM www.ncbi.nlm.nih.gov/entrez/ Gaucher \200\231s disease type 1 OMIM 230800 Gauch er \200\231s disease type 2 OMIM 230900 Gaucher \200\231s disease type 3 OMIM 231000 ICD-10 code E55.2 Other sphingolipidosis Patient advice \200 \200 Gaucher \200\231s disease is a recessively inherited condition. The prognosis is dependent on the exact gene mutation and is quite good with enzyme replacement therapy. References Vom Dahl S, Poll L, Di Rococco M, Ciana G, Denes C, Mariani G, Mass M. Evidence- based recommendations for monitoring bone disease and the response to enzyme replacement th erapy in Gaucher patients. Curr Med Res Opin 2006; 22: 1045 \200\22364. Treatment Enzyme replacement with macrophage targeted glucocer- ebrosidase reverses hematol ogical and hepatosplenome- EOSINOPHILIA-MYALGIA SYNDROME AND TOXIC OIL SYNDROME 520 Eosinophilia-myalgia syndrome and toxic oil syndrome De \201 nition Eosinophilia-myalgia syndrome (EMS), toxic oil syndrome and eosinophilic fa sciitis are united by the clinical features of eosinophilia and fasciitis. They should howe ver be con- sidered separate illnesses as toxins have been implicated in the development of EMS and Toxic Oil Syndrome but not eosinophilic fasciitis. The latter condition will be de aled with separately. and fatigue. By de \201 nition all patients suffered from myalgia and eosinophilia. Toxic oil syndrome usually manifest as an atypical pneu- monia with non-productive cough, p leuritic chest pain, headache, fever and pulmonary in \201 ltrates on CXR. Clinical features common to both conditions were pro- tean and included: Symptoms and signs \200 \200 \200 \200 \200 \200 \200 \200 \200 First de \201 ned in 1989 EMS was an epidemic associated with the ingestion of L-tryptopha n preparations from a sin- gle Japanese manufacturer (Showa Denko). L-tryptophan, an essent ial amino acid, has been available over the coun- ter since the 1970s and has been used to treat insomnia, depression and premenstrual symptoms. Myalgia. Arthralgia. Rash. Peripheral oedema. Cough. Dyspnoea. Fever. Alopecia. Neuropathy (sensory or sensorimotor involvement in a glove and stocking distribution). Hepatomegaly. Diagnostic criteria The US Centers for Disease Control and Prevention (CDC) de \201 ned th e syndrome according to 3 criteria: \200 \200 \200 Eosinophil count greater than 1000/mm . Incapacitating myalgia. Exclusion of other infecti ous or neoplastic illness that could account for the other two \201 ndings. Investigations \200 \200 \200 \200 \200 \200 Leucocytosis. Eosinophilia (>500 mm ). Elevated ESR. Elevated aldolase. Abnormal CXR. Abno rmal LFTs. Scleroderma-like skin change was unique to eosinophilia- Epidemiology EMS was initially described in 3 patients in New Mexico in October 1989. In ex cess of 1500 cases were subsequently reported within the US over the following two years. The syndrome occurred most commonly in Caucasian females over 35 years of age. The daily do se ranged from 10 \200\22315 000 mg (median 1500 mg) with the development of symptoms occur ring at a median of 127 days after \201 rst inges- tion of the formulation. It is worth n oting, however, that up to 14% of cases of EMS were not related to L-tryptophan. Neverthele ss, since the epidemic only a few incident cases have been described. myalgia syndrome. General investigations Relevant investigations to exclude differential diagnoses should be performed (see individual chapters). Salient investigation for the syndromes include: Eosinophilia (mandatory for EMS, although may be missed if present in early disease only). Leukocytosis. Raised IgE levels (toxic oil syndrome only). ANAs especially in EMS. Normal CK levels in almost all patients. Elevated aldolase. Abnormal LFTs common (transaminitis). Toxic oil syndrome was another epidemic occurring in Spain in 1981 which followed the inges tion of adulterated rapeseed cooking oil. The oil had been denatured with 2 percent aniline for industrial use, re \201 ned, then sold ille- gally as pure olive oil. \200 \200 \200 \200 \200 Etiology and pathophysiology Due to the epidemic nature of EMS and its association with a s ingle source of L-tryptophan, a contaminant was highly likely to be the culprit. This was s ubsequently found to be ethylidene bis[tryptophan] (EBT). Experiments revealed that mice ad ministered L-tryptophan from the batch in question developed myofascial thickening. Further analysis found a second contaminant (phenylamino)alanine to be associated with the conditi on. This was found to be chem- ically similar to an aniline derivative implicated in toxic oil syndrome. Imaging \200 \200 CXR: normal to acute in \201 ltrates, pleural effusion. Other helpful imaging modalities i nclude: MR brain, PFTs, EMG/NCS. Histology Histological analysis of affected tissue reveals: \200 Abnormal tryptophan metabolism in patients with both syndromes has been found however this may simply be a consequence of an in \202 ammatory response. Up-regulation of pro-in \202 ammatory cytokines is a feature. In addition, ex- cessive amounts of tryptophan inhibit hi stamine degrada- tion which leads to eosinophilia and myalgia. The exact pathogenesis of th e conditions however remains un- known. Capillary endothelial cell hyperplasia with swelling and necrosis. In \202 ammatory cell i n \201 ltrate in connective tissue, nerve, and muscle. Fibrosis particularly in the fascia . Differential diagnosis \200 \200 \200 \200 Churg \200\223Strauss syndrome. Eosinophilic pneumonia. Hypereosinophilic syndrome. Systemi c sclerosis. Clinical features EMS most commonly presented with a \202 u-like illness with marked myal gia and arthralgia as well as profound weakness CHAPTER 18 Miscellaneous diseases 521 \200 \200 \200 Resources Assessment tools Not applicable Polymyalgia rheumatica. Trichinosis. Hypothyroidism. Occult malignancy. Guidelines Not applicable Treatment Avoidance of the offending toxins was critical. Symptom- atic relief of the myria d clinical features was required as no drug was found to alter the natural history of the c ondi- tions. NSAIDs and corticosteroids were frequently used, especially in early disease. Chronic symptoms have been found to be extremely resistant to treatment. Patient organizations The National Eosinophilia-Myalgia Syndrome Network: http://www.nemsn. org/ ICD-10 codes M35.8 Other speci \201 ed systemic involvement of CTD Physiotherapy and occupational therapy was necessary for musculoskeletal manifestations and functional impair- ment. References Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996; 46: 81 \200\22391. Prognosis When L-tryptophan was recalled from the market in No- vember 1989, the incidence of EMS plummeted. The mor- tality rate for the \201 rst year was 2.7% for EMS and 1.5 \200\2233.6 % for toxic oil syndrome. Death resulted from progressive polyneuropathy and my opathy in the majority of patients with EMS. Both conditions were associated with long-term morbidity most commonly patients complaining of myalgia, muscle cramps, and neuropathy. On ly 10% of patients sur- veyed 4 years after disease onset were symptom free. Posada de la Paz M, Philen RM, Borda AI. Toxic oil syndrome: the perspective after 20 years. Epidemiol Rev 2001; 23: 231 \200\22347. Sullivan EA, Staehling N, Philen RN. Eosinophiliamyalgia syndrome among the non-L-tryptopha n users and pre-epidemic cases. J Rheumatol 1996; 23: I784 \200\2237. Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rape- seed oil denatured with aniline. Lancet 1981; 2: 567 \200\2238 Varga J, K h ri VM. Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related \201 brosing disorders. Curr Opin Rheumatol 1997; 9: 562 \200\22370. METABOLIC MYOPATHIES 522 Metabolic myopathies De \201 nition The metabolic myopathies are a diverse group of disorders characterized by abnormalities of skeletal muscle energy production. They arise as a consequence of inherite d de- fects in glycogen, lipid, purine, or mitochondrial metabo- lism. The term \200\230se condary metabolic myopathy \200\231 has been used to describe muscle damage from miscellane ous in- sults, such as drugs, toxins, and endocrinopathy. symptoms may allow prediction of the likely site of the abnormality. \200 FFAs are the principal muscle energy substrate at rest and during prolonged low intensity e xertion, e.g. walking. Lipid oxidation defects therefore tend to produce symp- toms several hours into moderate exercise or on fasting. Utilization of glycogen is necessary for more strenuous exertion, such as running, or on intense, isometric exer- cise, e.g. lifting weig hts. Disorders of glycogen metabo- lism typically cause symptoms within a few minutes of co mmencing vigorous exercise. In mitochondrial myopathies, muscle pain and fatigue may be pre cipitated by normal daily activities. Metabolic myopathies are traditionally managed within a neurology setting; however, it is i mperative that rheuma- tologists are aware of these diseases as they often mimic other cond itions, particularly in \202 ammatory myositis. Fur- thermore, they can be life threatenin g and are potentially treatable. The mechanisms by which these defects may lead to rhab- domyolysis are not well understood. In addition, the patho- logical processes underlying progressive muscle weakness are uncle ar. These patients tend to have more extensive glycogen or lipid deposition within muscle, which could potentially interfere with contraction; however, this is not universally seen. Epidemiology The metabolic myopathies are rare diseases and epidemio- logical data are limi ted. McArdle \200\231s disease is one of the more common with a prevalence of approximately one per 100 000. Symptoms may develop at any age, but usually appear in childhood or early adult life. Disorders of glycogen metabolism These conditions are commonly termed the \200\230glycogen storage disorders \200\231 or \200\230glycogenoses \200\231. They result from a variety o f enzyme defects leading to derangements in gly- cogen synthesis, glycogenolysis, or glycol ysis. \200 General clinical features Metabolic myopathies classically present with episodes of reversi ble muscle dysfunction induced by exercise. \200 Symptoms include muscle cramps, pain, weakness, stiff- ness, and myoglobinuria. Less common ly, they manifest as persistent, progressive muscle weakness. In rare cases, there may be a mixture of dynamic and permanent muscle symptoms. Children typically present with severe m ultisystem mani- festations, whereas adult-onset disease primarily affects muscles. Inheritance is autosomal recessive, with the exception of type VIII (hepatic form) and type IX, which are X-linked recessive traits. The clinical manifestations of these conditions a re extremely diverse, ranging from severe multisystem dis- ease in infancy to isolated prog ressive muscle weakness in the elderly. Amongst the more common of these, myophosphorylase (McArdle \200\231s disease) or phosphofructokinase (PFK) de \201 - ciencies typically caus e episodic muscle symptoms, whereas acid maltase or debranching enzyme de \201 ciencies ar e more likely to present with a progressive myopathy. Etiology and pathophysiology The speci \201 c genetic and biochemical abnormalities respon - sible for many of the metabolic myopathies have been iden- ti \201 ed. The majority are enzyme defects that lead to a block in muscle adenosine triphosphate (ATP) production. A ba sic understanding of muscle energy metabolism is fundamental to understanding the pathogene sis of these conditions. Overview of muscle energy metabolism Glycogen, glucose and free fa tty acids (FFAs) are the main substrates for muscle ATP production. \200 Myophosphorylase de \201 ciency (McArdle \200\231s disease) \200 Symptoms often develop in childhood but may not become clinically signi \201 cant until ad olescence Muscle fatigue, weakness and aching pain characteristi- cally emerge during the \201 rst few minutes of strenuous exertion Brief rest or intake of carbohydrate when sympt oms appear may subsequently improve exercise tolerance, termed the \200\230second wind \200\231 phenomenon. Acute, painful muscle contractures are seen. These differ from ordinar y cramps in that they solely occur on exer- cise, may last for hours, pain is exacerbated b y stretching the muscle and electrical activity is absent on EMG. Symptoms may culminate in muscle necrosis, myoglob- inuria (cola colored urine) and rarely renal failure. Muscle fun ction usually returns to normal between epi- sodes, although mild permanent weakness may de velop in long-standing disease. Glycogen is metabolized in the cytoplasm to pyruvate, which then diffuses into mitochondria . Short and medium chain fatty acids cross freely into the mitochondria. Long-chain fatty a cids require binding to carnitine for transportation across the mitochondrial membrane. Thi s process is mediated by the carnitine palmitoyltrans- ferases I and II. Within the mitocho ndria, oxidative decarboxylation of pyruvate and B-oxidation of FFAs results in acetyl- co- enzyme A formation, ultimately driving ATP production. Additional sources of ATP include an aerobic glycolysis (pyruvate is converted to lactate) and the purine nucle- otide cycle. Phosphofructokinase de \201 ciency (Tarui \200\231s disease) \200 Clinical presentation may be indistinguishable from McArdle \200\231s disease. Symptoms are exacerbated, rather than improved by carbohydrate intake. The potential for dysfunction Episodic muscle dysfunction may be the end result of de- fect s anywhere along the pathway. However, the pattern of CHAPTER 18 Miscellaneous diseases 523 Clinical features Reversible muscle symptoms are classically precipitated by prolonged mode rate exertion, e.g. walking, but may also be induced by fasting, cold exposure, infection, or general an- aesthesia. Muscle pain is a frequent symptom but cramps are less common than in the glycogenoses and acute, pain- ful contractures, and \200\230second wind \200\231 p henomena are not seen. \200 Table 18.5 Glycogenoses Type Enzyme defect Clinical features II Acid maltase (A-glucosidase) Debrancher Adult form: proximal myopathy with respiratory involvement III Hepatomegaly, hypoglycaemia, progressive myopathy Episodes of hypoketotic hypoglycaemia and coma may result from depletion of glycogen stores on fasting in conjunction with failure of hepatic conversion of fatty acids to ketoacids. Lipid deposition may lead to progressive myopathy, car- diomyopathy and fatty in \201 ltra tion of the liver. Abnormal tissue and serum carnitine levels. IV Brancher Hepatosplenomegaly, cirrhosis, cardiomyopathy, myopathy V Myo- phosphorylase Exercise intolerance, myoglobinuria VII Muscle PFK Exercise intolerance, myoglobinuria, haemolytic anemia VIII Phosphorylase b kinase Various types affecting liver, heart Muscle form: exercise intolerance, myoglobinuria Carnitine de \201 ciency syndromes \200 Primary muscle carnitine de \201 ciency causes a lipid storage myopathy. It usually presen ts in early life with progres- sive, proximal muscle weakness. Systemic carnitine de \201 ciency often presents in infancy. Features include recurrent episodes of hypoketotic hypogl ycaemia, encephalopathy, and cardiomyopathy. Muscle carnitine de \201 ciency may also be s een in mito- chondrial disorders or may be acquired, notably second- ary to haemodialysis o r drugs, e.g. valproate. IX PGA kinase Seizures, mental impairment Exercise intolerance, myoglobinuria X Muscle PGA mutase Exercise intolerance, myoglobinuria XI Muscle LDH Exercise intolerance, myoglobinuria XII Aldolase A Haemolytic anemia, exercise intolerance, myopathy BB-Enolase AMP-activated protein kinase Fatty acid transportation defects [carnitine palmitoyltrans- ferase (CPT) II de \201 cienc y] \200 XIII Exercise intolerance Cardiomyopathy, Proximal myopathy Commonest cause of recurrent rhabdomyolysis and myoglobinuria. The associated risk of acute tubular necrosis is higher than in the glycogenoses. Clinical manifestations are usually e vident by the age of 20, but may appear as late as the \201 fth decade. The Ser113Leu mut ation is found in 65% of patients. Episodic muscle pain and stiffness on sustained low inte nsity exercise or fasting is characteristic. Attacks of rhabdomyolysis may be life threaten ing due to respiratory failure, renal failure, or cardiac arrhythmias. Muscle function is u sually normal between attacks. PFK, phosphofructokinase; PGA phosphoglycerate; LDH, lactate dehydrogenase; *not yet classi \201 ed \200 May be a mild haemolytic anemia (phosphofructokinase is also found in red blood cells). Rar ely manifests as progressive myopathy in older adults. Acid maltase de \201 ciency (Pompe \200\231s disease) \200 \200 \200 De \201 ciency of lysosomal acid A-glucosidase. Classic infantile form is rapidly fatal. L ate onset variant manifests at any age from early child- hood onwards; onset as late as 68 has been reported. Prognosis improves with older age onset. Slowly progressive proximal mus cle weakness is almost universal and is the presenting symptom in 80%. Propensity for respi ratory muscle involvement. About 70% patients die from respiratory failure. May be increase d risk of cerebral aneurysm. Defects of oxidation enzymes These affect a variety of mitochondrial enzymes, including the short, medium, long, and very long-chain acyl-CoA de- hydrogenases (VLCAD), and produce a wide spectrum of clinical phenotypes. VLCAD de \201 ciency presents similarly to CPT II de \201 ciency and may be clinically indistinguishable. Disorders of purine metabolism Adenosine monophosphate (myoadenylate) deaminase (AMPD) de \201 ciency About 1.2 \200\2233.7% of the general population are homozygous for AMPD mutati ons and de \201 ciency of AMPD has been reported in up to 3% of muscle biopsies. However, the clinical signi \201 cance of this is debatable. It has been sug- gested that AMPD de \201 ciency may result in exercise intol- erance and myalgia in a subset of affected indivi duals. Conversely, the prevalence of AMPD de \201 ciency does not appear to be increased i n patients with muscle symptoms compared with the general population. Debranching enzyme de \201 ciency \200 \200 \200 \200 May cause progressive myopathy in the 2nd to 3rd decade. Weakness and wasting is often pred ominantly distal. Respiratory muscles are occasionally involved. A mild sensory axonal poly neuropathy is frequently seen. Disorders of lipid metabolism These include: \200 \200 Carnitine de \201 ciency syndromes: muscle or systemic. Fatty acid transportation defects: carnitine palmitoyltrans- ferase II de \201 ciency is the most common. Defects of B oxida tion enzyme. Mitochondrial myopathies These are a diverse group of multisystem diseases resulting from a bnormalities of the respiratory chain. Inheritance is either maternal or Mendelian accordin g to whether genetic defects affect mitochondrial or nuclear DNA. METABOLIC MYOPATHIES 524 This test carries a risk of rhabdomyolysis and a non- ischaemic version has been advocated. Glycogenoses cause absence or blunting of the normal rise in lactate (with the exception o f acid maltase, brancher and phosphorylase b kinase de \201 ciencies). Results are normal in disorders of lipid metabolism. Lactate and pyruvate may be elevated in mitochondrial myo pathies. Muscle involvement is common but the predominant symptoms are usually extra-muscular, e.g. blindness, deaf- ness, encephalopathy, ophthalmoplegia, and seizures. There are numerous re cognized syndromes, such as MERRF (myoclonic epilepsy with ragged red \201 bres), MELAS ( mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and PEO (pr ogressive external ophthalmoplegia). A subset of patients may present with progressive mus- cle weakness in the absence of overt systemic manifesta- tions, and a detailed family hist ory and thorough evaluation for potential associated features is therefore required. \200 Electromyography (EMG) \200 May show myopathic features in glycogenoses, especially in patients with progressive weakne ss. Marked insertional irritability may be evident in acid maltase de \201 ciency. Often n ormal in mitochondrial disorders and between symptomatic episodes in CPT II de \201 ciency . Investigation of metabolic myopathies Investigation beyond basic blood and urine tests is g ener- ally undertaken in a specialist setting. Further tests These should be directed by the clinical presentation. \200 Laboratory General \200 Carnitine levels may be abnormal in disorders of lipid metabolism. Serum and urine analysis for fatty acid metabolites is often informative. Enzyme testing in white blood cells or sk in \201 broblasts may be useful in acid maltase de \201 ciency. Identi \201 cation of t he responsible genetic defect is now possible in many of the metabolic myopathies. FBC: haemolytic anemia can occur in some glycog- enoses. LFTs, renal pro \201 le, bone pro \201 le, LDH, urate. Rhabdomyolysis may lead to elevated creatinine, potas- sium, urate, phosphate, and reduced calcium. Serum myoglobin may be detectable in acute rhabdomy- olysis , but is cleared rapidly (within 1 \200\2236 h). \200 Differential diagnosis of myopathy Muscle pain, fatigue, and cramps are ubiquitous complain ts, and it may be dif \201 cult to determine whether an underlying pathological process is likely. However, severe, aching pain on exertion, prolonged cramps, and myoglobinuria are suggestive of metabolic muscle disease. A thorough family history and evaluation for extram uscular features are man- datory. The numerous alternative causes for muscle cramps should also be considered, including: \200 \200 \200 \200 \200 \200 Creatine kinase (CK) \200 CK should be tested at rest and during acute attacks of muscle symptoms. Glycogenoses tend to cause a persistently raised CK. Elevation is usually mild to moderate, although CK may b e very high in acid maltase de \201 ciency. In lipid oxidation defects, CK is usually norm al between episodes of rhabdomyolysis. Electrolyte abnormalities: low calcium, magnesium. Peripheral vascular disease. Hypothyroid ism, hyperparathyroidism. Drugs/toxins, e.g. diuretics, statins, alcohol. Motor neuron dise ase: leg cramps are common. Peripheral neuropathy and radiculopathy. Urine myoglobin \200 Dark urine, positive for blood on dipstick, but with no red cells/casts on microscopy may i ndicate myoglobinuria. Semi-quantitative assay for haem pigments have approxi- mately 80% s ensitivity for myoglobin. Crucially, lack of detectable urine myoglobin does not exclude rh abdomyolysis. In patients presenting with progressive muscle weakness, the differential is wide and inclu des the idiopathic in \202 am- matory myopathies, muscular dystrophies, endocrinopa- thies , and drugs. Imaging MR and CT scanning have been utilized in glycogen storage disorders to characterize muscle pathology and are useful to guide muscle biopsy. Nuclear MR spectroscopy provides a n assessment of muscle metabolism, and may be useful in detecting glycolytic and mitochondr ial defects. Treatment General management strategies include: \200 \200 Avoidance of activities that precipitate symptoms. Dietary modi \201 cation: A high protei n diet and pyridoxine supplements have been advocated for McArdle \200\231s disease; howeve r, a recent Cochrane Review concluded there was insuf \201 cient evidence to recommend any speci \201 c intervention. A low fat, high carbohydrate diet with sup- plementary intake before exercise appears useful in CPT II de \201 ciency. Carnitine, ribo \202 avin, and m edium chain triglycerides have been trialed in disorders of lipid metabolism with some succ ess. Low dose creatine supplements have been shown to be bene \201 cial in McArdle \200 \231s disease, although higher doses appeared to be detrimental. Moderate intensity exercis e program have been shown to improve symptoms in mitochondrial disorders and glycogenoses a nd are likely to be helpful in other metabolic myopathies. Histology Muscle biopsy Diagnosis often rests on speci \201 c biochemical testing of muscl e tissue for enzyme activity. However, given the large number of potential defects, this sh ould be targeted ac- cording to initial clinical evaluation. Microscopy may reveal lipid or glycogen storage vacuoles but equally may be nor- mal. Ragged red \201 bres suggest mito chondrial myopathy, but are not pathognomonic. Other Forearm ischaemic lactate test \200 Involves exercising the forearm with an inflated blood pressure cuff in situ to create anae robic condi- tions, and serial blood tests for lactate, pyruvate, CK, and ammonia. CHAPTER 18 Miscellaneous diseases 525 Novel therapeutic strategies include enzyme replacement and gene therapies. Intravenous rec ombinant acid A-gluco- sidase has been shown to have bene \201 cial effects in acid maltas e de \201 ciency. Progress towards gene therapy has been made using animal models, althoug h it remains to be seen whether this is transferable to humans. Hanisch F, Joshi P, Zierz S. AMP deaminase de \201 ciency in skeletal muscle is unlikely t o be of clinical relevance J Neurol 2008;255: 318 \200\22322.