Adult Hallervorden–Spatz syndrome simulating amyotrophic lateral sclerosis

Abstract

Hallervorden-Spatz syndrome (HSS) is a neurodegenerative disorder characterized by progressive dementia, dystonia, ataxia, and rigidity. An atypical form of adult-onset HSS was observed in a 36-year-old man presenting with progressive dysarthria. Markedly dysarthric speech and a weak atrophic tongue associated with a neurogenic pattern of motor unit recruitment in bulbar-supplied muscles on electromyography led to an initial impression of bulbar amyotrophic lateral sclerosis (ALS). Lack of expected progression of symptoms, however, prompted reinvestigation. Repeat brain magnetic resonance imaging demonstrated an "eye-of-the-tiger" pattern in the basal ganglia, characteristic of HSS, thus requiring genetic studies. DNA analyses of the pantothenate kinase gene (PANK2) was conducted and revealed two novel, disease-causing exon 3 missense mutations (Cys231Ser and Tyr251Cys). This case broadens the genotypic and phenotypic spectrum of HSS to include a late-onset syndrome resembling bulbar-onset ALS.

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

“…At this stage, both groups display alterations consistent with neuronal distress and inflammation (HtrA2, Cx3cr1, Cnr2 and Mmp15 downregulation) and neurodegeneration, as is the case with Pantothenate kinase Figure 3 Bidimensional hierarchical clustering diagrams based on the list of variations identified by ANOVA comparison between the three groups of 110-day-old mice (p≤0.05) (Pank1) and endophilin 1 (SH3-domain GRB2-like 2). Notably, mutations in Pank1 are related to HallervordenSpatz syndrome, a neurodegenerative disorder characterised by progressive dementia, dystonia, ataxia and rigidity (Klepper et al 2003;Vasconcelos et al 2003). Finally, the gene encoding for a Gremlin-2 (Grem2) homolog was downregulated in the LSC of both SOD1-transgenic groups at 110 days.…”

“…Some variations may be indicative of neuronal distress such as Ste20/Stk39 downregulation. Other changes may be more directly involved in neurodegeneration-related events, such as endophilin-1/Sh3gl2 (Nonis et al 2008), GAP43 (Meyer et al 2009) and Pank1 (Klepper et al 2003;Vasconcelos et al 2003). Notably, a bone morphogenetic protein (BMP) antagonist, Grem2, is downregulated in both Tg groups.…”

Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: Clinical features and 99mTc-ECD brain perfusion SPECT findings

“…To date, 77 types of PANK2 mutations have been reported as being responsible for PKAN, including 47 types of missense mutations, nine types of nonsense mutations, 13 frameshift mutations, six mutations causing aberrant splicing, and two mutations causing an amino acid deletion [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In an extensive study on correlations between HSS phenotype and genotype in which an early-onset rapidly progressive childhood type was classified as a classic form, and other types of HSS were classified as an atypical form, it was shown that all patients with classic HSS and one third of those with atypical HSS had PANK2 mutations [5].…”

“…After mutations in the pantothenate kinase 2 (PANK2) gene were found to be responsible for HSS [4], several studies revealed significant correlations between clinical phenotypes and types of PANK2 mutations [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Among those studies, only four reports have described the detailed clinical features of the adult-onset slowly progressive type of PKAN with PANK2 mutations [13,14,17,18].…”

Racing against the clock: Recognizing, differentiating, diagnosing, and referring the amyotrophic lateral sclerosis patient

“…Other rare inherited disorders that should be considered in patients with symptoms of motor neuron degeneration include hexosaminidase A deficiency (adultonset Tay-Sachs disease), 30 spinocerebellar ataxia type 3 (Machado-Joseph disease), 31 neurodegeneration with brain iron accumulation (adult-onset HallervordenSpatz disease), 32 and polyglucosan body disease. 33 The ALS phenotype may be part of each of these disorders, but other neurological manifestations should prompt a more expansive differential diagnosis.…”