White matter involvement in a family with a novel PDGFB mutation

Case descriptions.

Patient IV-2.

A 5-year-old girl presented with her second unprovoked tonic-clonic seizure. The first episode occurred at age 2 years. She was born at term after an uneventful pregnancy and a normal delivery by healthy nonconsanguineous parents. Her psychomotor development and neurologic examination were unremarkable. The blood investigations and EEG were normal. Brain MRI revealed multifocal confluent white matter lesions and small cysts in the frontoparietal lobes (figure 1B). Head CT showed calcifications in the globi pallidi (figure e-1 at Neurology.org/ng). No treatment was given and the patient remained seizure-free over the years. However, she began to have attacks of sporadic migraine without aura at age 12 years. At age 14 years, brain MRI was unchanged. At age 17 years, cognitive functions and neurologic examination were persistently normal.

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Figure 1 Overview of the genetic and MRI data of the family and skin biopsy findings of individual III-5

(A) Pedigree and segregation analysis of PDGFB mutation. Individuals who underwent exome sequencing are indicated by arrows. PDGFB genotypes are reported under the symbols (wt, normal allele; mut, c.3G>C). (B) Case IV-2 (age 5 years): axial FLAIR brain MRI images demonstrate focal confluent areas of white matter hyperintensity in the frontal and parietal lobes associated with small cystic lesions (arrowheads). (C) Case IV-1 (age 22 years): coronal FLAIR images reveal similar focal confluent areas of white matter hyperintensity associated with small cystic lesions in the frontoparietal regions (arrowheads). (D) Case III-2 (age 44 years): axial T2-weighted images show confluent calcifications of lenticular, caudate, and pulvinar nuclei associated with multiple patchy hyperintensities of the periventricular and subcortical supratentorial white matter. (E) Case II-2 (age 73 years): coronal FLAIR images reveal scattered foci of white matter hyperintensity in the frontal and insular regions. (F) Case III-5 (age 42 years): axial FLAIR images reveal diffuse and patchy hyperintensities of the periventricular white matter with prevalent involvement of the frontal regions. (G) Electron microscopy of skin biopsy of individual III-5 showing an endothelial cell with areas of membrane fragmentation (arrowhead) and focal interruption (arrow) (magnification ×3,000). (H) High-resolution electron microscopy image of skin biopsy of individual III-5 showing basement membrane with thickened and fragmented areas (asterisks) (magnification ×7,000); EC = endothelial cell; FLAIR = fluid-attenuated inversion recovery; L = lumen.

Genetic study.

We performed exome sequencing in patients III-2 and IV-2 and selected rare nonsynonymous coding variants shared by the two affected relatives (figure 1A). We initially focused our analysis on the genes underlying autosomal dominant brain calcification (SLC20A2, XPR1, PDGFB, and PDGFRB) and vascular leukoencephalopathy (CADASIL, COL4A1, and COL4A2) and identified a G to C substitution affecting the first codon of the PDGFB gene (c.3G>C), which is expected to impair protein translation (table e-1). Segregation analysis of c.3G>C mutation was performed in 9 family members (figure 1A).

Discussion.

Twelve PDGFB mutations have been reported so far (table e-2). Brain calcifications are the main imaging findings.¹ We showed that white matter abnormalities may be an early and prominent imaging presentation. The c.3G>C mutation affects the first codon of PDGFB, similarly to a previously reported family, in whom, however, only CT scan data were available.⁴

Our patients had migraine without aura, which is often reported in PFBC, even in the absence of white matter abnormalities.¹ Although migraine may be associated with white matter hyperintensities cross-sectionally,⁶ at least in subject IV-2, migraine appeared several years after the finding of white matter abnormalities without evidence of progression over time.

PDGFRB and PDGFB mutations result in pericyte dysfunction and blood-brain barrier (BBB) impairment contributing to the development of brain calcifications and clinical manifestations, including migraine.¹ The perivascular contrast enhancement identified in 1 patient supports the pathogenic role of BBB dysfunction in this condition.

Small cysts were identified in the affected white matter of patients IV-2 and IV-1, similarly to genetic leukoencephalopathies, such as “COL4A1 mutation-related disorders.” It is interesting that the ultrastructural abnormalities reported in patients with COL4A1 mutation are similar to those depicted by skin biopsy electron microscopy of patient III-5.

The most recent classification of leukodystrophies and leukoencephalopathies lists 6 different conditions under the term genetic leukoencephalopathies related to vascular disorders, including COL4A1 mutation–related disorders.⁷

We suggest including white matter abnormalities related to PFBC mutations in the differential diagnosis of genetic leukoencephalopathies due to vascular disorders. The magnetic resonance finding of calcifications and small cysts may support the clinical suspect, especially in families with incomplete penetrance.