Morgan et al. (2006) studied a consanguineous Pakistani family with NBIA with 7 affected individuals in 5 generations. Affected individuals had abnormal iron accumulation in the globus pallidus, demonstrated by T2-weighted magnetic resonance imaging (MRI). The appearance was ... Morgan et al. (2006) studied a consanguineous Pakistani family with NBIA with 7 affected individuals in 5 generations. Affected individuals had abnormal iron accumulation in the globus pallidus, demonstrated by T2-weighted magnetic resonance imaging (MRI). The appearance was distinct from the 'eye of the tiger' sign seen in NBIA1 and Karak syndrome. Gregory et al. (2008) found that individuals with NBIA due to PLA2G6 mutations had widely varying phenotypes. They reported 6 affected individuals from 4 families. The average age at onset was 4.4 years. Presenting factors included gait instability or ataxia and speech delay; 2 were also noted to have diminished social interaction. Two-thirds of the patients had optic atrophy. Other features included spastic or areflexic tetraparesis, nystagmus, and seizures. Truncal hypotonia and strabismus were not observed. The natural history was characterized by progressive dystonia and dysarthria, as well as by neurobehavioral disturbances, including impulsivity, distractibility, poor attention span, hyperactivity, and emotional lability. Brain MRI showed cerebellar atrophy with high iron content in the globus pallidus. One of the patients reported by Gregory et al. (2008) was compound heterozygous for 2 mutations in the PLA2G6 gene (603604.0007 and 603604.0008). She presented at 3 years of age with toe walking and lower extremity spasticity. She developed optic atrophy and became nonambulatory by 5 years of age with dystonia and dysarthria, progressing to profound sensorimotor impairment by age 9 years. She died at age 23 years. Postmortem examination showed generalized brain atrophy with neuronal loss and gliosis. There were axonal swellings throughout the cortex, striatum, cerebellum, brainstem, and spinal cord. There were also Lewy bodies and neurofibrillary tangles, as seen in Parkinson disease (PD; 168600) and Alzheimer disease (AD; 104300), respectively. - Karak Syndrome In a family living in Karak, a town in southern Jordan, Mubaidin et al. (2003) observed 2 sons of consanguineous parents who showed early-onset progressive cerebellar ataxia, dystonia, spasticity, and intellectual decline. Neuroradiology showed cerebellar atrophy and features compatible with iron deposition in the putamen (including the 'eye of the tiger' sign) and substantia nigra. Although X-linked recessive inheritance was possible, the consanguinity and lack of other affected males in the maternal line favored autosomal recessive inheritance. Linkage analysis excluded a mutation in the PANK2 gene (606157). Mubaidin et al. (2003) suggested that this disorder, which they termed 'Karak syndrome,' was novel and a member of a family of neurologic diseases involving excess cerebral iron accumulation, including, in addition to NBIA1, neuroferritinopathy (606159), aceruloplasminemia (604290), and Friedreich ataxia (229300). In a review of NBIA, Gregory et al. (2009) stated that Karak syndrome falls into the phenotypic spectrum of atypical neuroaxonal dystrophy.
In the index patient from a large Pakistani family with NBIA, Morgan et al. (2006) found a homozygous missense mutation in the PLA2G6 gene (603604.0002). The mutation segregated with disease status in 15 affected and unaffected family members. ... In the index patient from a large Pakistani family with NBIA, Morgan et al. (2006) found a homozygous missense mutation in the PLA2G6 gene (603604.0002). The mutation segregated with disease status in 15 affected and unaffected family members. Gregory et al. (2008) found PLA2G6 mutations in 45 (79%) of 56 patients with INAD1 (NBIA2A) and in 6 (20%) of 23 patients with NBIA2B (see, e.g., 603604.0006-603604.0008). Patients with the less severe phenotype tended to have compound heterozygous missense mutations, consistent with residual protein function. - Karak Syndrome Morgan et al. (2006) demonstrated that the affected members of the kindred on the basis of which the Karak syndrome was named had a homozygous missense mutation in the PLA2G6 gene (603604.0005).