Childhood Dystonia-Parkinsonism Following Infantile Spasms—Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration

Abstract

Introduction Beta-propeller protein-associated neurodegeneration (BPAN) is a very rare, X-linked dominant (XLD) inherited member of the neurodegeneration with brain iron accumulation (NBIA) disease family. Case report We present a female case of BPAN with infantile spasms in the first year, Rett-like symptomatology, focal epilepsy, and loss of motor skills in childhood. Menarche occurred at the age of 9, after precocious pubarche and puberty.Dystonia-parkinsonism as extrapyramidal sign at the age of 10 years resulted in radiological and genetic work-up. Results Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) measured 66/120 points in body part-related dystonia symptoms. Cerebrospinal fluid examination showed dopamine depletion.T2 and B0 sequences of the diffusion-weighted magnetic resonance imaging showed susceptibility artifacts with NBIA-typical hypointense globus pallidus (GP) and substantia nigra (SN). Next-generation sequencing revealed a BPAN-causing pathogenic variant in WDR45 (WD repeat-containing protein 45) gene (c.830 + 1G > A, XLD, heterozygous, de novo). Skewed X-inactivation was measured (2:98). Conclusions Autophagy-related X-linked BPAN disease might still be underdiagnosed in female cases of infantile spasms.Skewed X-inactivation will have mainly influenced the uncommon, very early childhood neurodegenerative symptomatology in the present BPAN case. Oral levodopa substitution led to improvement in sleep disorder, hypersalivation, and swallowing.Reduced white matter and hypointense signals in SN and GP on susceptibility sequences in magnetic resonance imaging are characteristic radiological findings of advanced disease in NBIA. No BPAN-typical halo sign in T1-weighted scan at midbrain level was seen at the age of 11 years. NBIA panel is recommended for early diagnosis.

Rasmussen’s encephalitis and central precocious puberty. Neuroendocrinological characterization of three cases

“…Cases of CPP have been documented in neurodegenerative diseases such as mucopolysaccharidosis type I [23] and type III [24], neuronal ceroid lipofuscinosis [12], metachromatic leukodystrophy late infantile form [25] and Beta-propeller protein-associated neurodegeneration (BPAN) [26], where accumulation of toxic metabolites in blood and brain is hypothesized as a triggering event for CPP. It is possible that CPP in these entities is coincidental, but the number of cases from different neurodegenerative diseases, some being very rare disorders, could indicate a causal relationship.…”

“…It is possible that CPP in these entities is coincidental, but the number of cases from different neurodegenerative diseases, some being very rare disorders, could indicate a causal relationship. Various mechanisms have been hypothesized, including the accumulation of substances that interrupt the regulation of GnRH secretion leading to increased excitatory and decreased inhibitory factors, or selective destruction of inhibitory inputs resulting in increased GnRH secretion [12,26]. Recently, the neuroinflammation secondary to accumulation of substance produced as a result of metabolism and neurodegeneration in these entities [27] has also been suggested to be a possible factor involved in the disruption of regulatory hypothalamic tracts [28].…”