by Kurt Jellinger

General outline

NBIA 1 is a rare familial and sporadic progressive autosomal recessive neurodegenerative disease. Condition in wich extrapyramidal movement disorders are associated with a combination of neuroaxonaly dystrophy and iron accumulation in basal ganglie.

Synonyms

Hallervorden-Spatz disease, pantothenace kinase-associated neurodegeneration.

Symptoms and course

Slowly progressive gait disorders, stiffness, cramps in legs, muscular hypotonia, rarely progressing into rigidity, clubfoor, stuttering, speech and visual disorders rare. Delay of psychomotor development often antedates neurologic symptoms.

Hyperkinesia in around 50% of classical cases, rare in infantile and late-infantile forms. These show choreatic, athetotic, dystonic disorders, tremor, occasional rest tremor. Frequent dystonia. Parkinsonism in late cases. Dysarthria, dysphagia, eye movement disorders.

Other symptoms include ataxia, nystagmus, optic atrophy and rare seizures. Early-infantile cases present with psychomotor retardation, seizures, followed by progressive rigidity, spasticity with/without dystonia.

Ataxia, terminating in stiffness and dementia.

Rare adult cases show ataxia, rigidity, athetosis, akinetic-rigid parkinonism, with or without dementia, rarely early-onset dementia. According to onset of disorder, one distinguishes:

• Infantile forms (onset 1st year of life);
• Late-infantile casses (onset 2-3 years; death at age 8-16 yrs);
• Juvenile “classic” HAD (onset between age 7-15 years; duration 6-20 yrs);
• Adult or late cases (onset between age 22-64 years, duration 3- months to 13 years with death up to age 70 years).

Course with slow progression of clinical signs and symptoms.

Causes and risk factors

Due to mutations of PANK 2 (pathothenate kinase), mapped on chromosome 20p13 or other mutations. PANK is a rate-determining enzyme in coenzyme A biosynthesis.

Another, similar disorder was mapped to chromosome 19q13.3 that contains the gene for fertitin light peptide (FTS). This “new” disease was called “neuroferritinopathy”. In patients reported as HARP syndrome, changes in exon 5 of PANK 2 gene were seen. Risk factors are consanguinity in families, and missense mutations in PANK 2 gene.

Frequency

Rare disorder, around 100 published cases. No incidence or prevalence data available.

Diagnostic procedures

Laboratory tests and blood chemistry are unremarkable. CerebroSpinal Fluid (CFS) may show increased non-protein bound iron. Electromyograph (EMG) may show rigidospasticity. CCT shows highs signal lesions in globus pallidus; MrI T-2 weighted images show marked decreased intensity in globus pallidus and nigra due to increased iron and feritin content, and small hyperintensive area in internal segment (gliosis and tissue vacuolation).

This “eye-of-the-tiger” signal is of great diagnostic value, particularly in late-infantile forms. Familial cass may show acanthocytosis and retinitis pigmentosa. After IV iron application, decreased uptake of 59 Fe is seen in basal ganglia. ß-CIT and IBZM-Spect, in contras to PD and MSA, shows normal bbasal ganglia; PET shows significant hypoperfusion in head of caudat enucleus, pons and cerecbellum with normal dopaminergic function of basal ganglia.

Care and treatment

Causal treatment is unknown. Symptomatic strategies include L-Dopa and dopamine agonists showing limitied efficacy. Trials with iron-chelators gave negative results.

Ongoing research/Clinical trials

To elucidate the pathogenic and molecular genetic backgrounds of HAD and related disorders and iron accumulation in brain.

Available services

Departments of neurology.

References

• K.A.Jellinger, J. Duda: Hallervorden-Spatz disese. In; Neurodegenertion. DW Dickson et al. (eds) ISN edition, Los Angeles 2003 (in press).OMIM #234200 (update 09/18/2002)
• Gordon N. Euro J Peadatri. Neurol 6:243, 2002
• Racette BA et al. Mov Disord 16:1148-52 (2001)
• Ching KH et al. Neurology 58:1673-74 (2002)