Rare Genetic Causes of Stroke

Introduction

Cerebrovascular diseases constitute the fourth leading cause of death in the United States annually and the third leading cause of mortality in developed countries . In addition, it is the number one cause of permanent disability globally and the second most common cause of dementia . Many risk factors for cerebrovascular diseases have been established including nonmodifiable factors such as age, gender, and race, as well as acquired risk factors such as hypertension, smoking, diabetes, and obesity. These factors, however, only account for a portion of the stroke risk suggesting that other variables, including genetics, must be involved in the etiology of stroke.

The exact contribution of genetics to the incidence of stroke still remains largely unknown; however, it is clear that stroke can result from both monogenic and polygenic diseases. Common monogenic causes of stroke include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its autosomal recessive form, CARASIL, as well as sickle cell disease, and Fabry disease. These diseases are covered elsewhere in this book. This chapter focuses on the rarer monogenic and polygenic causes of stroke, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), homocystinuria, moyamoya disease, and inherited connective tissue disorders, including type IV collagen α1-chain gene ( COL4A1 ) mutation, Marfan syndrome, and vascular Ehlers–Danlos syndrome (VEDS).

Monogenic Diseases

About 5% of stroke cases result from monogenic disease; however, this number likely underestimates the true number of cases as there are upward of 50 single gene causes of stroke . Some of these gene mutations result in stroke as a part of a systemic syndrome, while some others result in clinical manifestations limited to the central nervous system (CNS) . The more common monogenic diseases associated with stroke are summarized in Table 107.1 .

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

Genetic Basis . The genetic basis for MELAS results from mutations in a number of different mitochondrial or nuclear genes associated with the respiratory chain. Despite several gene mutations being reported, around 80% of all MELAS patients have an A3243G point mutation in the leucine mitochondrial transfer RNAs (tRNAs) . Additionally, there have been three other tRNA point mutations reported including two others in the leucine tRNA gene, the T3271C and A3260G mutations, and one in the lysine tRNA gene, A8344G . Other mutations include a mitochondrial DNA deletion and mutations to different respiratory chain genes including the ND4 gene , the cytochrome c oxidase subunit III gene , and the ND5 gene .

Clinical Findings . MELAS is a multiorgan disease. However, different cells have different amounts of mutated mitochondrial DNA (heteroplasmy) and tissue-specific metabolic requirements. In addition, MELAS has significant genotypic heterogeneity. These factors explain the variations in severity and organ involvement seen among patients. The most striking feature of MELAS are the stroke-like episodes where patients present with focal deficits, including hemianopia, aphasia, hemiparesis, and cortical blinding . Further, vomiting, headache, and seizures can be seen during exacerbations. MELAS has been associated with another mitochondrial disease, MERRF, which is characterized by myoclonic epilepsy with ragged-red fibers . Because of the disruption in the respiratory chain and mitochondrial dysfunction, blood lactate levels and lactate/pyruvate ratio are elevated. In some cases, lactic acid levels may be normal in the blood but increased in the CSF, particularly during stress. Additional clinical findings include muscle weakness, ptosis, pigmentary retinopathy, sensorineural hearing loss, neuropsychiatric disorders, cardiomyopathy, and diabetes . Brain imaging studies reveal bilateral calcifications in the basal ganglia. Stroke-like episodes correlate with MRI/CT findings consistent with cerebral infraction. These lesions are typically asymmetric, localize to the parietal and/or occipital lobes, and do not follow a well-defined vascular territory . Noninvasive angiographic studies are usually unrevealing. Proton magnetic resonance spectroscopy can identify regions with decreased N -acetyl-aspartate and increased lactate-to-creatine ratio consistent with decreased neuronal viability and anaerobic metabolism, respectively.

Disease Course . MELAS often has an onset as early as the teenage years with stroke-like episodes. The course of the disease, however, is highly variable ranging from asymptomatic with normal early development to insidious onset, rapid disease progression, and premature death as early as the fourth decade of life .

Diagnosis . MELAS patients usually have decreased respiratory chain enzyme activity in skeletal muscle. Mitochondrial DNA sequencing can be performed on blood, skeletal muscle, urinary sediment, hair follicles, and buccal mucosa. However, due to the process of heteroplasmy, the load of mutated DNA varies among tissues and may be, in some cases, undetectable. Therefore, a negative genetic screening test does not necessarily rule out the diagnosis of MELAS. The muscle biopsy may demonstrate ragged red fibers that are considered the histological hallmark of this condition. These fibers stain positive to Gomori trichrome and cytochrome oxidase. In addition, they may have areas of increased succinate dehydrogenase staining suggestive of mitochondrial dysfunction and compensatory proliferation. On electron microscopy, affected tissue shows increase in number and size of mitochondria with paracrystalline bodies.

Management . Unfortunately, there are no current successful treatment strategies for MELAS; however, numerous approaches have been tried including dietary supplementation with vitamins and coenzymes and administration of redox compounds. Most therapies that have been utilized aim at improving the function of the respiratory chain and have included coenzyme Q10 , nicotinamide , combination therapy of cytochrome c/vitamin B1/vitamin B2 , idebenone , and sodium dichloroacetate , among others. Nonetheless, these therapies have only demonstrated marginal benefit to these patients. More recently, the supplementation with arginine has been shown to decrease the severity and frequency of stroke-like episodes. A bolus of arginine 0.5 g/kg given within 3 h of symptom onset followed by 0.5 g/kg administered as a continuous infusion for 24 h for the next 3–5 days is recommended for MELAS patients presenting with signs or symptoms suggestive of metabolic stroke. In addition, long-term prophylaxis with a daily dose of arginine 0.15–0.30 g/kg administered orally in three divided doses is recommended for MELAS patients with history of stroke .