Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.329544
Source of Support: None, Conflict of Interest: None
Keywords: CARASIL, cerebral small vessel disease, HTRA1 gene, north India
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), also known as Nemoto disease or Meada syndrome, is an uncommon genetic disorder affecting the small blood vessels in the brain. CARASIL is a single-gene disorder known to be caused due to mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). This HTRA1 protein normally represses transforming growth factor-beta (TGF-β) family signaling and its mutation results in vascular changes.
CARASIL is a very rare disease with most previous cases reported from within Asia and a few documentations from the western world., The true prevalence is unknown. Distinctive features of the disease include an early adulthood (20-30 years) onset of a non-hypertensive cerebral small vessel disease (CSVD) (23% develop stroke before the age of 40 years), with rapidly progressive disability in cognitive and motor domains, behavioural and mood changes such as easy irritability and apathy, in association with extra-neurological manifestations, like premature alopecia and spondylosis. After the onset of neurological symptoms, the disease progresses slowly over 5- 20 years. The neuroimaging of the brain shows diffuse leukoencephalopathy and multiple subcortical infarcts. The primary purpose of this brief report is therefore, to increase awareness about this inherited cause of stroke in young as well as to compile and extend the spectrum of Indian literature on this uncommon entity.
We report a 46 year-old lady, non-diabetic and non-hypertensive, with no history of addictions, married and having one live male child, and history of two first trimester abortions. The patient presented with sudden onset change of speech 2 months back, not however associated with any difficulty in swallowing. Speech was slurred and effortful with intermingling of words. No progression of dysarthria was seen for the last 2 months. The patient also had mild weakness and heaviness in the right upper and lower limb for the last 2 months. A detailed history revealed that the patient had chronic low backache for the last 4 years, relieved partially with analgesics and physiotherapy and there was radiation of pain to the left lower limb for the last 1 year. There was also a prior long standing history of alopecia for the last 30 years beginning in her adolescence. No history of previous strokes, seizures or fever was obtained. Enquiry regarding family history revealed that she is third in the order among six siblings. A history of teenage onset alopecia and backache was present in two elder sisters, two younger brothers had late onset alopecia starting at around 35 years of age and youngest one advised neurosurgery for lumbago. There was no history of similar illness in father, mother, or offspring of siblings.
On general physical examination, patient had sparse, thin hair [Figure 1] and mild spinal tenderness in lumbar region, rest of the examination was unremarkable. Neurological examination revealed normal higher mental function with Mini Mental State Examination 29/30 and Frontal Assessment Battery 18/18. Speech was spastic, with normal fluency, comprehension, naming and repetition. Motor system examination findings were mild spasticity of upper and lower limbs (right > left side), normal power and brisk reflexes with flexor plantar response. Sensory and cerebellar testing was normal. Gait was normal except for subtle dragging of the right lower limb.
Magnetic resonance imaging (MRI) brain revealed extensive periventricular symmetrical T2 and FLAIR hyper intensities along with the involvement of external capsule, pons, with anterior temporal lobe [Figure 1]. Pons showed the classic “arc sign” showing hyper intense lesion extending from pons to middle cerebellar peduncles, more visible on the right side. Computed tomography angiography brain and neck vessels revealed no abnormality. MRI gradient echo showed micro bleeds. Work up for vasculitis including ANA, Anti-dsDNA, and ANCA profile were negative. Cerebrospinal fluid examination was normal. Visual evoked potentials were normal. MRI spine done for lumbago revealed multiple disc dessications, prolapsed lower lumbar intervertebral discs and reduced vertebral heights [Figure 1].
In view of clinical setting of non-hypertensive stroke-like episodes in the absence of common risk factors, extensive MRI white matter hyper intensity pattern, the patient was planned for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CARASIL genetic panel testing. Our patient's genetic analysis disclosed that she has CARASIL, having a homozygous mutation on exon 2 variant c.523G>A (p.Val175Met) of HTRA1 gene. She was explained regarding the disease and genetic counselling was done. Siblings were made aware of symptoms of the disease. The patient was prescribed conservative treatment for her symptoms and advised regular neurology outpatient follow-up.
Monogenic disorders may account for nearly 1% of all ischemic strokes and include conditions like CADASIL, CARASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; others being Fabry disease, sickle cell disease, rheumatologic diseases, and vasculitis. CARASIL, in 1976, was initially described as a “familial unusual encephalopathy of Binswanger's type without hypertension”. However, it is now considered a triad of alopecia, spondylosis deformans, and young adult onset dementia following leukoaraiosis caused by cerebral small-vessel disease.
Reviewing Indian literature on CARASIL [Table 1],,, we found that CARASIL has been previously described in three families and two sporadic patients.,
While most of them presented in their second and third decade, our patient presented late at 46 years of age, with sudden onset spastic speech and right sided stiffness, history of adolescence onset alopecia and low back pain for the last 3 years. Thus, her symptoms were clinically milder and of a shorter duration compared to others. Besides, there was neither history of parental consanguinity, nor any cognitive decline, emotional incontinence or behavioral issues at the time of presentation unlike previous probands. Also, siblings had affection in terms of alopecia and lumbago, but had no CNS manifestation yet.
Our patient only had findings suggestive of pyramidal involvement, with normal higher mental functions, intact cranial nerves, normal cerebellar and gait testing. Thus, dementia attributable to the cerebral damage was not yet manifest.
MRI brain in our patient was however, similar to previous cases, with extensive symmetrical T2 and FLAIR hyper intensities in periventricular white matter along with anterior temporal lobe, external capsule and pons involvement. Pons had an incomplete “Arc Sign” showing hyper intense lesion extending from pons to middle cerebellar peduncles, more visible on the right side. Thus, characteristic MRI with a slightly incomplete “arc sign” was present, previously described in only two of the previous cases.
Genetic workup was done only in one study, which showed three mutations in HTRA1—c.739delG (p.E247Rfs) in family 1, c.830_831delAG (p.E277Vfs) in family 2, and c.502A>T (p.K168ter) in family 3. However, the mutational analysis in our case revealed HTRA1 gene homozygous mutation on exon 2 variant c.523G>A (p.Val175Met). Western literature is presently expanding on the novel varieties of HTRA 1 mutations studied and their correlations with clinical manifestations in patients of CARASIL; however, owing to sparse reporting and limited genetic studies, no such conclusions in Indian patients can be presently made. Nevertheless, this mutation locus “c.523G>A (p.Val175Met)” is uncommon in affected individuals as per genomic database of HTRA1 mutations, and hence this report strengthens its temporal association with causation of the disorder.
We, therefore emphasize that with a clinical set up of early onset non hypertensive CSVD, family history of alopecia and back pain and MRI hyperintensities in bilateral symmetrical subcortical white matter, basal ganglia, internal capsule, and brainstem, one should think of genetic causes and CARASIL testing should be done. Once diagnosed, this would prevent patients from unnecessary prolonged antiplatelet therapy, and genetic counselling can then be done.
Treatment includes general supportive care, including education about the illness and emotional support, both for the patient and their families. Walking aids, pharmacological treatment for spasticity, mood stabilizers, and appropriate management of dementia and psychiatric manifestations are also suggested.
Genetic counselling is essential as each sibling of the proband has a 25% chance of being affected, carrier testing for at-risk family members, and prenatal testing for pregnant relatives, should be carried out when indicated.
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Conflicts of interest
There are no conflicts of interest.