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.

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:

• 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

• brainstem atrophy

  • uncommon feature and likely seen as a late feature

• 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 available and symptomatic management and specialist screening is recommended ^3,4.

Differential diagnosis

General imaging differential considerations include ^3,6:

• ​hypertensive microangiopathy

• CNS vasculitis