Is it all about genes?

By: Dr Nicolas Martinez-Majander, Affiliation: Department of Neurology, Helsinki University Hospital, Finland

A 44-year-old woman with no comorbidities was admitted to the emergency due to a slowly progressive vertigo and mild left sensorimotor hemiparesis. She is a mother of three, never-smoker, and exercising frequently. She had just returned from maternal leave and had noticed some minor difficulties in learning new procedures at work. She had no medical history of epileptic seizures or migraine with or without aura.

Toxicology and infection screen were negative and she was normoglycemic and normotensive. On the neurological examination, the patient showed only mild ataxia in left extremities with a sense of numbness and tingling. Initial MRI showed widened perivascular spaces with bilateral multiple older small lacunar infarcts, as well as extensive white matter abnormalities. Also hyperintensity of the anterior temporal lobes was evident in T2 sequences typical to CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Arterial imaging remained unremarkable. Diagnosis of CADASIL was later confirmed with genetic testing.

Several single gene mutations have stroke (ischemic and/or hemorrhagic) as their primary or secondary feature, the most common being CADASIL. It is caused by autosomal dominant NOTCH3 mutations on chromosome 19, typically with recurrent lacunar strokes, whilst hemorrhagic strokes are less frequent. Clinical features include migraine with aura, cognitive impairment, mood disorders, and seizures. Migraine is present in up to 40% of patients and stroke occurs typically during the fourth and fifth decade. Diagnosis is based on MRI findings, skin biopsy and/or genetic testing. However, there is no specific treatment for CADASIL.1,2

CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoence-phalopathy has MRI findings similar to CADASIL, but the disease is caused by a HTRA1 gene mutation encoding for a serine protease. CARASIL usually causes early-onset muscle spasticity, alopecia, lower back pain, and about half of the patients have a stroke or similar episodes before age of forty. As with CADASIL, cognitive impairment, and mood and personality changes develop as the disease progresses. The exact prevalence of CARASIL is unkown.3

Another disease to keep in mind is Fabry disease, which commonly results from a single point mutation of the GLA gene. However, this gene is located on the X chromosome. The mutation leads to a lysosomal alpha-galactosidase deficiency and to a progressive accumulation of glycosphingolipids within lysosomes of cells in various organ systems. Clinical manifestations include ischemic and hemorrhagic stroke, angiokeratoma, acroparesthesias, renal dysfunction, cardiac failure (hypertrophy, restrictive cardiomyopathy, arrhythmias, and valvular heart diseases), hearing loss, tinnitus, vertigo, bowel dysfunction etc. First symptoms are usually experienced in early childhood, but the delay from symptom onset to diagnosis (genetic testing for the GLA gene) can take years due to the rarity of Fabry. However, unlike in CADASIL and CARASIL, a specific treatment with enzyme replacement therapy can prevent/slow down disease progression.4 According to prior reviews, Fabry disease may explain up to 1% of all stroke in the young, including 3-5% of cryptogenic strokes.5

Furthermore, DNA mutations in mitochondrial genes (in >80% of cases point mutation in mtDNA A3242G) may lead to mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This should be suspected especially in patients with seizures, focal neurological deficits, migraine-like headaches, and encephalopathy. MELAS patients may also present with cardiac diseases, short stature, diabetes mellitus, muscle weakness, and dementia. Imaging might show lesions that do not follow known arterial territories, especially in parietal and occipital lobes.

In addition to these, several mutations with autosomal inheritance have been identified, including e.g. familial moyamoya (mutations in ACTA2, MTCP1, or RNF213), retinal vasculopathy with cerebral leukodystrophy (RVCL, mutations in TREX1), deficiency of adenosine deaminase 2 (associated polyarteritis nodosa vasculopathy, mutations in ADA2), and homocystinuria (mutations in MTHFR, MTR, MTRR, or MMADHC).

In conclusion, these single gene mutations are not common but should be kept in mind when treating especially patients with early-onset cryptogenic strokes. Although most of them do not have specific treatment, the knowledge of hereditary disease may give patients and their family members reassurance and opportunity to treat other modifiable risk factors early enough.




  1. Desmond DW et al. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke 1999;30(6):1230–1233.
  2. Donato D et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Med 2017;15(1):41-017-0778-8.
  3. Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke Cerebrovasc Dis 2011;20(2):85-93.
  4. Zarate YA et al. Fabry’s disease. Lancet 2008;372(9647):1427-1435.
  5. Shi Q et al. Prevalence of Fabry disease in stroke patients–a systematic review and meta-analysis. J Stroke Cerebrovasc Dis 2014;23(5):985-992.
  6. El-Hattab AW et al. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015;116(1-2):4-12.