Inherited metabolic disorders and cerebral infarction

Review

Inherited metabolic disorders and cerebral infarction Expert Rev. Neurother. 8(11), 1731–1741 (2008)

Kavita Kalidas and Réza Behrouz† † Author for correspondence Vascular & Critical Care Neurology, Department of Neurology, University of South Florida College of Medicine, 2A Columbia Drive, 7th Floor, Tampa, FL 33606, USA Tel.: +1 813 259 8577 Fax: +1 813 259 8551 [email protected]

The association of genetic factors and cerebral infarction (CI) has long been established. A positive family history alone is a recognized risk factor for CI and vascular events in general. However, there are certain inherited conditions that further increase the risk of stroke. These conditions are generally metabolic and mitochondrial genetic defects that have variable modes of inheritance. This article reviews major inherited metabolic disorders that predispose an individual to CI. Ten main conditions will be discussed: Fabry’s disease, cerebrotendinous xanthomatosis, tangier disease, familial hypercholesterolemia, homocystinuria, methylmalonic acidemia, glutaric aciduria type I, propionic acidemia, ornithine transcarbamylase deficiency and mitochondrial encephalopathy, lactic acidosis and stroke-like phenomenon. Keywords : cerebral infarction • cerebrotendinous xanthomatosis • Fabry’s disease • familial hypercholesterolemia • glutaric acidemia • homocystinuria • MELAS • metabolic disease • methylmalonic acidemia • ornithine transcarbamylase deficiency • propionic academia • stroke • Tangier disease

A family history of stroke is an independent risk factor for stroke [1] . There are certain inherited metabolic disorders that increase the risk of cerebral infarction (CI) beyond the traditional vascular risk factors and are generally associated with an earlier onset of CI. Categorically, these disorders are characterized by early or premature atherosclerosis caused by defects in biolipid or amino acid metabolism, cerebrovascular occlusive disease resulting from accumulation of non-metabolized substrates, or conditions that cause brain ischemia strictly at the molecular level (metabolic stroke). In this review, Mendelian and mitochondrial metabolic disorders associated with CI are discussed (Table 1) . Disorders of biolipid metabolism Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with abnormally high total serum cholesterol and low-density lipoprotein (LDL) levels. The condition is caused by absent or malfunctioning LDL receptors (LDL‑R) whose gene is located on chromosome 19. Mutations occur in either the LDL‑R or the apolipoprotein B (APO‑B) gene, although more common in the former (1000 mutations identified in LDL‑R and nine in the APO‑B gene) [2] . These mutations cause impaired removal of serum LDL by the liver which is accomplished by receptor-mediated www.expert-reviews.com

10.1586/14737175.8.11.1731

endocytosis. There is a twofold increase in serum LDL concentration in heterozygotes and a fivefold increase in homozygotes [3] . Heterozygous FH (HeFH) affects approximately one in 500 people [4] . There is a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner descents [5] . FH with homozygous state occurs very rarely with a prevalence of one in a million individuals [6] . The clinical phenotype of FH has been shown to be associated with accelerated atherosclerosis, leading to premature cardiovascular and cerebrovascular disease. The onset of vascular events in the heterozygous population is generally at approximately 40 years of age in men and approximately 50–60 years in women. [7,8] . There are also cholesterol deposits affecting the cornea, eyelids and extensor tendons [4] . Tendon xanthomas are present in more than 70% of patients by age 50 years [9] . Corneal arcus, a white or gray halo in the corneal margin, may be a sign of FH in younger patients [9] . These features have a much earlier onset in the homozygous form of the disease [10] . Premature internal carotid artery (ICA) atherosclerosis leads to steno-occlusive or artery-to-artery embolic infarcts [11] . However, the relationship between FH and intracranial cerebrovascular disease is less established [12,13] . The diagnosis of FH is based on clinical findings, an autosomal dominant family history pattern of early cardiovascular disease, and elevated

© 2008 Expert Reviews Ltd

ISSN 1473-7175

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LDL and total cholesterol levels. Total cholesterol levels in FH heterozygotes average 325–450 mg/dl [9] . In a patient younger than 20 years of age with an affected first-degree relative, a LDL level of more than 155 mg/dl suggests the diagnosis [14] . Confirmation is based upon molecular genetic testing. Statins are the first choice treatment for all patients with heterozygous and homozygous FH [15–18] . The efficacy and tolerability of simvastatin at doses up to 80 mg/day are well established and is cost effective in the management of FH patients [19] . Life expectancy of patients with FH is reduced by 15–30 years unless they are effectively treated with lipid-lowering agents [19] . The addition of ezetimibe, a cholesterol absorption inhibitor, to statins does not seem to significantly affect intima-media thickness in these patients [20] . In patients with homozygous FH, LDL

apheresis has been long advocated [21] . Combining atorvastatin with LDL apheresis may have added benefit for prevention of atherosclerosis in patients homozygous for FH [22] . Fabry’s disease

Fabry’s disease (FD) is an X‑linked disorder of lysosomal storage with an estimated incidence between 1/40,000 and 1/117,000 live births [23] . FD is caused by a deficiency in the enzyme α‑galactosidase A, which is involved in breakdown of globotriaosylceramide (Gb3). Accumulation of Gb3 in vascular endothelial cells and smooth muscle cells is responsible for phenotypic presentation of FD, which affects several organs including the skin, kidney, nervous system, cornea and heart. Subsequently, the disease is characterized by angiokeratomas, renal insufficiency, corneal opacities (cornea verticillata), painful small

Table 1. Clinical features associated with inherited metabolic disorders with stroke. Disorder

Inheritance

Defect

Age

Radiologic features

Clinical features

Familial hypercholesterolemia

Autosomal dominant

LDL receptor

By 40 years

Large and small artery CI

Tendon xanthomas Corneal arcus

Fabry’s disease

X-linked

a-galactosidase A deficiency

16–50 years

Large and small artery CI Pulvinar sign

Angiokeratomas Renal insufficiency Cornea verticillata Cardiomyopathy Neuropathy

Cerebrotendinous xanthomatosis

Autosomal recessive

27-sterol hydroxylase deficiency

13–40 years

Large and small artery CI, dentate nuclei

Bilateral cataracts Achilles tendon xanthoma Diarrhea, Dementia

Tangier disease

Autosomal recessive

Apolipoprotein A1 deficiency

Middle age


Neuropathy Enlarged orange-colored tonsils

Homocystinuria

Autosomal recessive

Cystathione b-synthase deficiency or MTHFR deficiency

Any age


Ectopia lentis Skeletal abnormalities Osteoporosis

Methylmalonic acidemia

Autosomal recessive

Methylmalonyl CoA mutase deficiency

Neonatal to adulthood

Cerebellum and basal ganglia

Hepatomegaly Hypotonia Encephalopathy

Glutaric aciduria type I

Autosomal recessive

Glutaryl CoA dehydrogenase deficiency

6–18 months Striatal necrosis

Macrocephaly Dystonia, choreoathetosis

Propionic acidemia

Autosomal recessive

Propionyl CoA carboxylase deficiency

Infancy to adulthood

Bilateral basal ganglia

Pancreatitis Hypogammaglobulinemia Osteopenia Bone marrow suppression

Mitochondrial encephalopathy, lactic acidosis and stroke-like phenomenon

Mitochondrial

Mutation at base pair 3243 for leucine on transfer RNA

Less than 15 years

Not within vascular territories Cortical Basal ganglia calcifications

Headaches Seizures Easy fatigability

Orthinine transcarbamylase deficiency

X-linked

Ornithine transcarbamylase deficiency

Cingulate gyrus Severe: and insular cortex neonatal Mild: infancy to adulthood

Neurocognitive changes Seizures Hyperammonemic coma

CI: Cerebral infarction; CoA: Coenzyme A; LDL: Low-density lipoprotein.

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Inherited metabolic disorders & cerebral infarction

fiber polyneuropathy, cardiomyopathy and ischemic strokes. The disease is more severe in men and has been reported in all ethnic groups [24] . Cerebral infarction is a major complicating manifestation of FD and occurs in both hemizygote males and heterozygote females [25] . Ischemic strokes generally take the form of small artery infarcts and most often occur before the age of 40 years [26,27] . The mean age at onset of cerebrovascular symptoms is 33.8 years for homozygous patients and 40.3 years for heterozygotes [25] . The rate of cerebrovascular complications in FD is estimated at 24% [27] . A cohort study reported a high frequency of FD in patients with cryptogenic stroke, corresponding to approximately 1.2% in young stroke patients [28] . Pathologically, there is progressive stenosis and occlusion of small vessels owing to Gb3 deposition within the intima and media of the cerebrovasculature. Brain MRI may reveal numerous silent lesions. A so-called ‘pulvinar sign’, which is increased intensity in the posterior aspect of the thalamus on T1-weighted MRI, is highly specific for FD [29] . Subcortical infarcts and diffuse white matter disease can be demonstrated even on the MRI of female carriers [30] . Transcranial Doppler (TCD) analysis of patients with FD indicates that early cerebrovascular symptoms arise from small vessel occlusion and not from embolic sources from large arteries or the heart [31] . Although subject to debate, there appears to be a higher frequency of infarctions in the vertebrobasilar territory [25,28] . Elongated, ectatic, tortuous vertebral and basilar arteries are common angiographic features of FD [25] . Misdiagnosis of FD is common and the mean delay from onset of symptoms to correct diagnosis is 13.7 and 16.3 years in males and females, respectively [32] . Affected males are diagnosed by assessing the level of α‑galactosidase A activity in plasma or peripheral leukocytes. Affected females may have normal to very low levels of α-galactosidase A activity and genetic testing is therefore is required [33] . Recombinant human α‑galactosidase A replacement therapy has proven to be a groundbreaking treatment for patients with FD [34] . TCD evaluation of patients with FD has shown significantly improved cerebral blood flow velocities with enzyme replacement therapy [35] . Chronic alteration of the nitric oxide pathway in FD demonstrated by PET is also reversible with enzyme replacement therapy [36] . The treatment is commercially available worldwide but is relatively expensive. No systematic investigation exists to suggest that the use of antiplatelet agents carry any benefit in prevention of CI in patients with FD. Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare but treatable autosomal recessive disorder caused by 27-sterol hydroxylase (CYP27) deficiency. The gene for CYP27 is localized on the long arm of chromosome 2. CYP27 plays an important role in cholesterol metabolic pathways by mediating the oxidation of sterol intermediates. Patients with CYP27 deficiency have defective bile acid synthesis and abnormally high levels of cholestanol in the blood, urine and other tissues. www.expert-reviews.com

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Clinical manifestations of CTX include cataracts, diarrhea, Achilles tendon xanthoma, progressive neurological impairment and atherosclerotic vascular disease [37] . Premature atherosclerosis can potentially lead to cardiovascular and cerebrovascular complications [38–40] . Abnormally low levels of high-density lipoprotein (HDL) in CTX may contribute to increased atherogenesis and excessive deposits of tissue sterols in face of low or low-normal concentrations of plasma cholesterol and LDL [41] . Not all neurological manifestations of CTX are due to vascular atherosclerosis. Progressive accumulation of cholestanol in the brain (brain xanthomas) is thought to be the main mechanism responsible for cerebral symptoms in CTX [42] . The prevalence of CTX owing to CYP27 mutation R362C is approximately one per 50,000 among white individuals [43] . CTX is mainly diagnosed by its clinical symptoms, especially neurologic disease and Achilles tendon xanthomata [44] . Elevation of serum cholestanol and urinary bile alcohols with low-to-normal serum cholesterol establishes the diagnosis [45] . Achilles tendon biopsy may reveal the presence of cholestanol. MRI shows typical bilateral and symmetrical hyperintensities involving the dentate nuclei [46] . Chenodeoxycholic acid (CDCA), a bile acid, is the most effective therapy in CTX, and long-term therapy with this agent may correct the biochemical abnormalities, and arrest and possibly reverse the progression of the disease [47] . A combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol and lathosterol in adult CTX patients [48] . Tangier disease

This extremely rare autosomal recessive condition is characterized by low levels of APOA1 (less than 1%) and HDL (less than 5% of normal) [49,50] . Tangier disease (TD) is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) on chromosome 9q31 [51] . Less than 100 cases have been described worldwide. Patients with TD have a reduced ability to transport cholesterol out of their cells which leads to severe deficiency of serum HDL and accumulation of cholesterol in many tissues [52] . Although the main neurologic manifestation of TD is neuropathy, premature atherosclerosis can lead to cardiovascular and cerebrovascular diseases, especially in middle aged and elderly Tangier homozygotes [53] . Tangier homozygous patients have a four- to sixfold increased risk of atherosclerotic cardiovascular disease compared with age-matched controls [54] . In Tangier heterozygotes, the prevalence of cardiovascular disease is 60% higher than unaffected relatives [55] . A peculiar clinical finding is the presence of enlarged orange-colored tonsils. Diagnosis of TD is made by combining the clinical picture of polyneuropathy, enlarged orange tonsils and atherosclerosis with laboratory findings. Low levels of APOA1 and cholesterol in the serum, and undetectable levels of HDL and LDL cholesterols in the blood confirm the diagnosis of TD [56] . Treatment of TD is supportive. To date, no definitive therapy has been identified to slow the process of atherosclerosis in patients with TD. 1733

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Disorders of amino & organic acid metabolism

Methylmalonic acidemia

Homocystinuria

Methylmalonic acidemia (MMA) is an autosomal recessive inborn error in metabolism of isoleucine, valine, methionine and threonine. It is caused by a deficiency of the methylmalonyl‑CoA mutase, or by a defect in the biosynthesis of its cofactor, adenosylcobalamin [72] . The defect is in the ability to convert methylmalonyl‑CoA into succinyl‑CoA [73] . Excessive amounts of methylmalonic acid (MM) are found in blood, urine and cerebro spinal fluid. There are two forms of enzymatic defect: mut(o) with no detectable enzymatic activity and mut(-) with reduced activity [72] . The prevalence of MMA is estimated to be one case per 50,000 and the gene is located on chromosome 6p21 [74,75] . Clinical presentation of MMA may vary from a severe neonatal form with acidemia and death, to a progressive chronic disease [72] . Non-B12-responsive phenotype and mut(o) present during infancy. Infants are normal at birth, but soon develop lethargy, vomiting, dehydration, hepatomegaly, hypotonia and encephalopathy [76] . The B12-responsive and mut(-) phenotype occur in the first year of life [76] . B12-responsive MMA patients are generally considered a distinct group with a better prognosis [77] . Metabolic strokes have been reported in patients with MMA [78,79] . The pathophysiology of CI is thought to be due to inhibition by high levels of MM of succinate dehydrogenase, an enzyme essential for mitochondrial aerobic glucose oxidation [80] . This leads to a fall in cellular ATP generation and, subsequently, excitotoxicity [80] . Combined MMA and HCU (cobalamin C disease) can exist in an individual, further increasing his or her risk for CI [81] . Prenatal diagnosis of MMA can be achieved by using MS–MSbased screening [82] . Other laboratory features that support the diagnosis of MMA are elevated serum MM, glycine, ammonia and homocysteine [83] . MRI may reveal acute or subacute infarctions involving bilateral globi pallidi [84] . Management of MMA includes restricted whole protein intake, vitamin B12, bicarbonate, carnitine, metronidazole and maintenance of caloric consumption with a metabolic formula [79] . Liver, kidney and combined liver–kidney transplants have been reported for the treatment of MMA [85] . Because of the non-atherogenic pathophysiology of strokes in MMA patients, antiplatelet drugs have no role in this clinical scenario.

Homocystinuria (HCU), an autosomal recessive defect in metabolism of the amino acid methionine, is the most common cited hereditary metabolic disease associated with CI [57] . The gene to this disorder has been mapped on chromosome 21q22.3. Classic HCU is due to deficiency of the enzyme cystathionine‑β synthase (CBS). In total, 92 different disease-associated mutations have been identified in the CBS gene [58] . The two most frequently encountered of these mutations are the pyridoxineresponsive I278T and the pyridoxine-nonresponsive G307S [58] . HCU also can result from a severe deficiency of the enzyme methylenetetrahydrofolate reductase (MTHFR) [59] . Homocystinuria is characterized by a marked increase in serum and urinary homocysteine, and the clinical phenotype is comprised of mental retardation, thromboembolism, ectopia lentis, skeletal abnormalities, osteoporosis and premature atherosclerosis [60] . Patients with HCU usually have ‘Marfanoid’ body configurations. The first major signs of the disease occur at a mean age of 13 years, although most patients with HCU do not necessarily present with thromboembolism in the absence of other signs of the disease [61] . The worldwide frequency of classic HCU is approximately one in 344,000 live births and it occurs in all ethnic groups [62] . Patients with HCU have markedly elevated plasma homocysteine concentrations, and increased risks of stroke and coronary artery disease [63] . Cerebrovascular disease including CI is a prominent feature of HCU and it has been determined that a causal relationship exists between serum homocysteine concentrations and CI [64] . Thromboembolism of both small and large arteries and veins can occur [65] . High homocysteine concentrations are thought to impair endothelial function, increase oxidative stress, impair methylation reactions and alter protein structure [66] . Approximately 50% of patients experience a thromboembolic event by the age of 30 years [60] . However, CI can be the presenting symptom and occur as early as the first year of life [67] . Aside from artery-to-artery embolism, craniocervical dissection is an important etiology of CI in these patients [68,69] . The diagnosis of HCU may be delayed by a mean interval of 11 years between the first major signs of the disease and the ultimate diagnosis [61] . Quantitative tests for homocysteine in urine and blood are available commercially, and measurement of CBS activity in cultured fibroblasts provides definitive support for the diagnosis [70] . Tandem mass spectrometry (MS–MS) can be used for neonatal screening of HCU [71] . MRI is nonspecific and may show large or small vessel infarcts in any vascular distribution. Patients with HCU who are responsive to pyridoxine should be treated with daily pyridoxine, folic acid and vitamin B12. Patients who do not respond to pyridoxine should be treated with a low methionine diet and supplemented with cysteine, folate and vitamin B12. Betaine, a methyl donor, is sometimes used as adjunctive therapy. Antiplatelet therapy should be considered for every patient with HCU and a history of CI [60] . 1734

Glutaric aciduria type I

Glutaric aciduria type I (GA‑I) is an autosomal recessive dis order with an incidence of approximately one in 30,000 [86] . This disorder is due to a deficiency of glutaryl‑CoA dehydrogenase (GCDH), an enzyme involved in catabolism of lysine, hydroxylysine and tryptophan. The GCDH gene is localized on chromosome 19p13.2 and more than 150 disease-causing mutations have been identified [87] . As a result of a biochemical pathway block, glutaryl-coenzyme A (CoA) is shunted into an alternate metabolic pathway resulting in accumulation of glutaric acid, 3‑hydroxyglutaric acid and glutarylcarnitine in the urine. Clinically, patients with GA‑I lack characteristic signs and symptoms prior to the onset of the first encephalopathic crisis. However, progressive macrocephaly has been identified in 75% of Expert Rev. Neurother. 8(11), (2008)


patients during infancy [87] . Between the ages of 6 and 18 months, patients develop an acute neurologic crisis. This usually occurs after a high catabolic state such as an acute illness with fever, poor oral intake and vomiting. These encephalopathic crises characteristically lead to bilateral striatal damage visualized as focal, stroke-like hyperintensities on MRI, and clinically manifesting as dystonic or dysk inetic movement disorders with dysarthria and choreoathetosis [88] . The striatal necrosis in this condition is suggested as being similar to lesions secondary to hypoxic–ischemic injury and intoxication with 3‑nitroproprionoc acid [89] . The mechanism of striatal injury is that 3‑hydroxyglutaric acid crosses the compromised BBB acting as a respiratory chain toxin. Energy metabolism is inhibited and a vasculopathic process ensues [89] . The diagnostic test of choice is measurement of glutaryl‑CoA dehydrogenase activity in fibroblasts or lymphocytes [88] . Other tests include urine screen for glutaric acid and much smaller amounts of 3‑hydroxyglutric acid. MRI may demonstrate frontotemporal atrophy with widened sylvian fissures, and abnormal signal hyperintensities in the basal ganglia and subcortical white matter [88,90] . Overall, GA‑I patients have a poor long-term prognosis. Most show slow improvement, but many patients do not recover fully from a neurologic crisis and residual morbidity may be significant with hypotonia, ataxia, choreoathetoid movements, spasticity, dystonia and dyskinesia [86] . Treatment consists of a diet deficient in lysine, hydroxylysine and tryptophan but with supplements of carnitine and riboflavin, and with aggressive treatment of other infections [88] . Baclofen and anticholinergics have been used for dystonia with some success. Propionic acidemia

Propionic academia (PA) is a rare disorder of amino acid metabolism caused by deficient activity of the biotin-dependent enzyme, propionyl CoA carboxylase (PCC). As a result, there is an accumulation of propionic acid in the body. The mode of inheritance for PA is autosomal recessive and the gene is localized to chromosomes 13 (PCC α‑subunit) and 3 (PCC β‑subunit) [91] . There are various forms of clinical presentation: severe neonatal, chronic intermittent or slow and gradual [92] . The condition sometimes presents in the first few days of life with vomiting, ketoacidosis, hyperammonemia, hyperglycinemia and lethargy, with progression to coma [93] . Other manifestations include hypogammaglobulinemia, bone marrow suppression, osteopenia, pancreatitis and cardiomyopathy [94] . Mortality in infancy is high but the disease may continue into adulthood with recurrent episodes of metabolic decompensation [95] . PA can also have a purely neurological presentation [93] . The estimated incidence of PA is one in 350,000 and there is an unusually high prevalence of this disease in Saudi Arabia (one per 2000 to one per 5000 live births) [96,97] . Metabolic strokes in patients with PA typically involve the bilateral basal ganglia [97–99] . PET studies have demonstrated decreased uptake of 18 Fluoro-2-deoxyglucose (18FDG) in the basal ganglia at later stages of the disease [100] . MRI may show changes involving the bilateral basal ganglia [101] . These strokes usually occur during episodes of metabolic decompensation. www.expert-reviews.com

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The diagnosis of PA is by urinalysis for amino acids and organic acids. Glycine, 3‑hydroxypropionate, methylcitrate, tiglylglycine, propionylglycine, 2‑methylacetoacetate, 2‑methyl3-hydroxybutyrate, 3‑oxovalerate and 3‑hydroxyvalerate should be increased in the urine [102] . The diagnosis of PA is confirmed by demonstrating propionyl CoA carboxylase deficiency in skin fibroblasts [103] . Chronic management of PA includes restriction in natural proteins, carnitine and biotin supplementation, and alkaline therapy for chronic acidosis [92] . Severe hyperammonemia that is unresponsive to medical management is treated with dialysis. Some patients may eventually require liver transplantation [96] . Mitochondrial encephalopathy, lactic acidosis & stroke-like phenomenon

Mitochondrial encephalopathy, lactic acidosis and stroke-like phenomenon (MELAS) is a syndrome caused by a specific mitochondrial mutation clinically defined by a constellation of exercise intolerance, onset of symptoms before age 40 years, encephalopathy frequently with dementia and seizures, ragged red fibers seen on muscle biopsy, lactic acidosis and stroke-like manifestations [104,105] . The stroke-like manifestations are unique to MELAS, allowing this syndrome to be clinically distinguished from other mitochondrial syndromes. In approximately 80% of MELAS cases, a mutation at base pair 3243 affecting the transfer RNA for leucine is identified, and in 10% of cases a separate point mutation at base pair 3271 has been localized [106] . The population prevalence of the MELAS 3243 mutation is estimated at 236 per 100,000 [107] . Mitochondrial DNA (mtDNA) has a maternal inheritance and demonstrates heteroplasmy, indicating that within a single organ or cell, both normal and mutated mtDNA may be present. Therefore, the replicative potential of the cell should be considered when searching for the specific mtDNA point mutation [108] . Skeletal muscle replicates at a slower rate, and hence it is more likely to contain a higher concentration of the mutated DNA [109] . There is a large phenotypic variation and age of onset in patients with MELAS. This is thought to be due to the difference in the percentage of mutant mtDNA found in different tissues [108] . Symptoms of MELAS include muscle weakness (87%), easy fatigability (15–18%) recurrent headaches and seizures (28%) [104] . The common features of MELAS related to stroke include acute stroke at onset, characteristically between ages 5 and 15 years, and may include focal manifestations such as hemiparesis, hemianopia or cerebral blindness, and nonfocal features such as episodic headache and vomiting [110] . Acute imaging abnormalities on CT scan and MRI are multiple areas of low attenuation that do not correspond to any major cerebral vascular territory and are migratory in nature [104,111] . There appears to be a propensity for the posterior cerebrum, typically affecting the temporal, parietal and occipital lobes [104,111] . MRI may also reveal particular abnormalities specific for MELAS, with multifocal laminar cortical pattern hyperintensities sparing the deep white matter. Classically, these are distinct from thromboembolic strokes that involve both the gray and white 1735

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matter of a single vascular territory [110] . Another differentiating feature between arterio-occlusive CI and stroke-like episodes of MELAS is the appearance on the apparent diffusion coefficient (ADC) MRI. In MELAS-related ‘strokes’, abnormalities appear as increased signal on the ADC, while arterio-occlusive CI generally expresses a low signal [112] . Other CT and MRI findings of MELAS patients include basal ganglia calcifications and generalized cortical atrophy [110] . Cerebral angiography is normal in the majority of patients, even in regions of cortical hypodensities seen on CT. Angiography does not show evidence of occlusive changes supporting the theory that stroke-like episodes of MELAS are nonvascular in origin [108] . The pathogenesis of stroke-like episodes in MELAS syndrome remains unclear, but there are two currently proposed theories. One theory suggests that the development of a mitochondrial angiopathy due to failure in mitochondrial function leads to an abnormal accumulation of mitochondria within vascular endo thelial and smooth muscle cells, resulting in impaired oxygenation and glucose extraction, with subsequent tissue damage contributing to stroke-like episodes [108,113] . The second theory involves abnormalities in cerebral capillaries due to the abnormal mitochondria located in the subendothelial spaces, resulting in narrowing of capillary lumens and decreased blood flow to affected areas [108] . Cardiac dysfunction as a result of mitochondrial abnormalities in cardiac cells may contribute to impaired circulation seen in MELAS patients, but this is not thought to be the primary factor causing the stroke-like syndrome. Treatment for patients with MELAS is primarily supportive and there is no specific consensus criteria established. Seizures are usually managed with antiepileptics including phenobarbital, phenytoin, gabapentin, lamictal and benzodiazepines [114] . Treatment of MELAS includes idebenone and coenzyme Q10 that act as electron carriers in the respiratory chain of mitochondria [114] . Coenzyme Q10 is suggested to improve symptoms of muscular weakness and peripheral nerve damage [108,114] . Disorders of urea cycle Ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency (OTCD) is an X‑linked disorder that results from mutations in the OTC gene located on the short arm of the X chromosome within band Xp21.1 [115] . Ornithine transcarbamylase is an enzyme that catalyzes the conversion of citrulline from carbamyl phosphate and ornithine. With an incidence ranging from one per 14,000 to one in 80,000, OTCD is the most common form of urea acid cycle disorder [116,117] . Although the condition occurs primarily in hemizygous males, heterozygous females may also be affected with varying degrees of severity (asymptomatic to severe disease) [118] . The onset of OTCD is unpredictable, and clinical manifestations may present at any point from the neonatal period (hemizygous males) through to adulthood. In the neonatal male, the condition is likely to be lethal owing to abolished enzymatic activity [119] . The adult-onset form of OTCD has been reported in patients in their fifth or sixth decades of life, although with milder symptoms [120] . 1736

Biochemical consequences of OTCD include hyperammonemia, hyperglutaminemia, hypoargininemia and hypocitrullinemia. Clinically, these biochemical derangements range from coma and death in the neonate to severe encephalopathy due to hyperammonemia. Psychiatric symptoms, seizures, anorexia and emesis are other symptoms that may be present in a patient with OTCD [121] . Stroke-like episodes (metabolic strokes) have been reported in patients with OTCD, which may or may not parallel rises in serum ammonia levels [122–124] . The mechanism for these strokes is not clearly understood, but deficits in energy metabolism and glutamate-mediated excitotoxicity have been proposed [125] . Brain imaging studies are nonspecific but may demonstrate ischemic changes involving various parts of the cerebral cortex, including the cingulate gyrus and insular cortex [126] . Diagnosis of OTCD may be challenging, especially if the patient is asymptomatic (generally females). A high clinical index of suspicion and a judicious utilization of laboratory testing is paramount. The primary laboratory abnormality is elevated serum ammonia levels, characteristic of all urea cycle disorders [127] . There may be elevated levels of ornithine, glutamine and alanine, and relatively low citrulline levels. Low citrulline levels are not necessary diagnostic of OTCD [128] . Elevated urinary orotidine and/or ortotic acid levels, especially after challenge with allopurinol, are helpful in diagnosis of heterozygote females [129] . The test is safe and quick, but its reliability has been questioned in detecting carriers [130] . Whenever there is any doubt in diagnosis of OTCD in asymptomatic carriers, genetic testing should be undertaken. Treatment of OTCD consists of a low-protein diet to reduce serum ammonia levels and arginine [131] . Arginine treatment has been shown to reduce hyperammonemic attacks in late-onset OTCD [131] . Episodes of hyperammonemia require hospitalization for intravenous sodium benzoate and sodium phenylacetate therapy [118] . In life-threatening situations, liver transplantation may be considered [119] . The prognosis of OTCD is better for those with an onset after infancy, but morbidity from brain damage does not appear to be linked to the number of episodes of hyperammonemia that have occurred [119] . Expert commentary

The clinical features associated with these conditions are diverse and CI is perhaps the most incapacitating sequela. It is essential for physicians to maintain a heightened sensitivity to the possibility of an inherited metabolic etiology when evaluating young patients with CI, especially in the presence of other unusual systemic manifestations, early atherosclerosis or family history of young strokes. Although treatment options for these conditions are limited, the availability of effective therapy for some of these disorders serves as the major impetus for early diagnosis. Newborn screening is a powerful tool to diagnose presymptomatic infants. Unfortunately, not all the diseases discussed are included in neonatal mass screening programs. Since early diagnosis and appropriate treatment can prevent the otherwise poor Expert Rev. Neurother. 8(11), (2008)


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prognosis, it may be justifiable to include diseases such as GA‑I in neonatal mass screening programs. Para-neurological signs and symptoms may also help solidify the diagnosis, especially if the disorder occurs with conspicuous cutaneous manifestations. Finally, a family history always serves as a clue when considering syndromes associated with early-onset CI. With continuous advancement in genetic and cell-based technologies, the discovery of novel etiologic mechanisms to metabolic diseases will hopefully unveil new targets for therapy. Perhaps in the future, gene therapy could become the definitive modality in treatment of inherited metabolic diseases.

investigation are novel methods allowing accurate diagnosis of these disorders. This will ultimately impact healthcare cost by a significant reduction in false-positive results and prevention of complications related to inherited metabolic disorders. One such complication is CI, which can present itself anytime during the course of these conditions. By early screening and meticulous medical and dietary care, this disabling consequence of metabolic disease may be prevented. Lastly, we continue to rigorously investigate the prospects of gene therapy which someday may become the ultimate solution to management of these conditions.

Five-year view

Financial & competing interests disclosure

Our knowledge of inherited metabolic disorders continues to grow as we expand our endeavors in early and effective screening, timely recognition of symptoms and state-of-the-art imaging. Advances in newborn screening protocols have proven invaluable in diagnosis of inborn errors of metabolism in both the presymptomatic and symptomatic phases. Currently under

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Metabolic disorders associated with cerebral infarction have variable modes of inheritance. • Most of these disorders are associated with an enzymatic defect. • Cerebral infarction associated with inherited metabolic disorders can occur as a result of accelerated atherosclerosis, vascular infiltrative disease or oxidative stress. • Compared with patients with traditional vascular risk factors, cerebral infarction in patients with inherited metabolic disorders often occurs early in life. • Neonatal screening can determine the risk of premature vascular events in affected individuals. • Close follow-up and medical care of affected individuals may potentially reduce the risk of cerebral infarction. • Medical care of patients with inherited metabolic disorders is conducted via a multidisciplinary approach. • Treatment options for inherited metabolic disorders are limited.

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Rubba P, Mercuri M, Faccenda F et al. Premature carotid atherosclerosis: does it occur in both familial hypercholesterolemia and homocystinuria? Ultrasound assessment of arterial intima-media thickness and blood flow velocity. Stroke 25, 943–950 (1994).

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Grewal RP. Stroke in Fabry’s disease. J. Neurol. 241, 153–156 (1994).

•

Good review of cerebrovascular manifestations of Fabry’s disease.

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Moore DF, Altarescu G, Ling GS et al. Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 33, 525–531 (2002).

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Moore DF, Scott LT, Gladwin MT et al. Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 104, 1506–1512 (2001). Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH. Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations. Arch. Neurol. 59, 527–529 (2002).

•

Good review of cerebrotendinous xanthomatosis.

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Valdivielso P, Calandra S, Durán JC, Garuti R, Herrera E, González P. Coronary heart disease in a patient with cerebrotendinous xanthomatosis. J. Intern. Med. 255, 680–683 (2004).



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Asztalos BF, Brousseau ME, McNamara JR, Horvath KV, Roheim PS, Schaefer EJ. Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease. Atherosclerosis 156, 217–225 (2001).

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•

Also a good review of stroke genetics.

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•• Very concise review of stroke genetics. 61

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van Guldener C, Stehouwer CD. Homocysteine and large arteries. Adv. Cardiol. 44, 278–301 (2007).

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Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girls with ornithine transcarbamylase deficiency. N. Engl. J. Med. 335, 855–859 (1996).

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Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur. J. Paediatr. Neurol. 7, 115–121 (2003).

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Christodoulou J, Qureshi IA, McInnes RR, Clarke JT. Ornithine transcarbamylase deficiency presenting with strokelike episodes. J. Pediatr. 122, 423–425 (1993).

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Very good review on mitochondrial encephalopathy, lactic acidosis and stroke-like phenomenon (MELAS).

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129

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Review

Affiliations •

Kavita Kalidas, MD Resident Physician, Department of Neurology, University of South Florida College of Medicine, 2A Columbia Drive, 7th Floor, Tampa, FL 33606, USA Tel.: +1 813 259 8577 Fax: +1 813 259 8551 [email protected]

•

Réza Behrouz, DO Assistant Professor, Vascular & Critical Care Neurology, Department of Neurology, University of South Florida College of Medicine, 2A Columbia Drive, 7th Floor, Tampa, FL 33606, USA Tel.: +1 813 259 8577 Fax: +1 813 259 8551 [email protected]

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