Pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) is an autosomal dominant monogenic COL4A1-related disorder that primarily causes cerebral small vessel disease. It is a distinct entity to COL4A1 brain small-vessel disease, but very likely on the same spectrum of disease as Swedish hereditary multi-infarct dementia.
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Epidemiology
The exact prevalence is unknown, but the condition is considered very rare. The onset of symptoms is generally in young and middle-aged adults.
Clinical presentation
The clinical presentation consists of :
focal neurological deficits accumulated from acute infarcts, e.g. pontine stroke syndromes or lacunar stroke syndromes 1
progressive dementia 2-4
Unlike other COL4A1-related disorders, extra-cranial manifestations are generally not seen 4.
Pathology
PADMAL is caused by a mutation to the 3' untranslated region of the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 2,3,5. In PADMAL, this mutation leads to over-expression in COL4A1, which is distinct to mutations causing COL4A1 brain small-vessel disease which are generally missense mutations in different regions of the same gene leading to abnormal alpha-1 chain of type IV collagen synthesis 2,3,5.
Radiographic features
MRI
MRI is the investigation of choice and demonstrates the following features 1-6:
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white matter lesions and ischemic strokes (lacunar infarcts), predominantly affecting the pons (most common), subcortical white matter, periventricular white matter, basal ganglia, and corpus callosum
involvement of the cervical cord has also been rarely described 6
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brainstem atrophy
uncommon feature and likely seen as a late feature
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cerebral microhemorrhages, particularly in the pons and subcortical white matter
uncommon feature
intracerebral (macro)hemorrhage is very rare
CTA/MRA
Angiographic studies are usually normal 1.
Treatment and prognosis
No specific disease-modifying treatment is currently available and symptomatic management and specialist screening is recommended 3,4.
Differential diagnosis
General imaging differential considerations include 3,6:
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