Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype associated with dysarthric speech, mental retardation, and varying degrees of cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest this phenotype. In two families (A and D), shared homozygosity among affected relatives mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the reelin signaling pathway involved in neuroblast migration in the cerebral cortex and cerebellum. Sequence analysis of VLDLR revealed nonsense mutation R257X in family A and singlenucleotide deletion c2339delT in family D. Both these mutations are predicted to lead to truncated proteins lacking transmembrane and signaling domains. In two other families (B and C), the phenotype is not linked to chromosome 9p. Our data indicate that mutations in VLDLR impair cerebrocerebellar function, conferring in these families a dramatic influence on gait, and that hereditary disorders associated with quadrupedal gait in humans are genetically heterogeneous.genetics ͉ Unertan syndrome O bligatory bipedal locomotion and upright posture of modern humans are unique among living primates. Studies of fossil hominids have contributed significantly to modern understanding of the evolution of posture and locomotion (1-5), but little is known about the underlying molecular pathways for development of these traits. Evaluation of changes in brain activity during voluntary walking in normal subjects suggests that the cerebral cortices controlling motor functions, visual cortex, basal ganglia, and the cerebellum might be involved in bipedal locomotor activities (6). The cerebellum is particularly important for movement control and plays a critical role in balance and locomotion (7).Neurodevelopmental disorders associated with cerebellar hypoplasias are rare and often accompanied by additional neuropathology. These clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathology, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal abnormalities, and cutaneous disorders, among others (8). Quadrupedal locomotion was first reported when Tan (9, 10) described a large consanguineous family exhibiting Unertan syndrome, an autosomal recessive neurodevelopmental condition with cerebellar and cortical hypoplasia accompanied by mental retardation, primitive and dysarthric speech, and, most notably, quadrupedal locomotion. Subsequent homozygosity mapping indicated that the phenotype of this family was linked to chromosome 17p (11). Thereafter, three additional families from Turkey (12-14) and another from Brazil (15) with similar phenotypes have been described, and video recordings illustrating the quadrupedal gait have been made (10-12). Here, we report that VLDLR is the gene responsible for the syndrome in two of these four Turkish families and report additional gene mapping st...

The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.

The results suggest that low blood Mg level and high blood sodium level may be risk factors for HDH. Magnesium supplementation may help patients with HDH whose serum Mg levels are found to be low.

Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebrocerebellar structures required for posture and gait in humans.

Guillain-Barré syndrome is a relatively common, acute, and rapidly progressive, inflammatory demyelinating polyneuropathy. The diagnosis is usually established on the basis of symptoms and signs, aided by cerebrospinal fluid findings and electrophysiologic criteria. Previously, radiologic examinations have been used only to rule out other spinal abnormalities. We report a case of systemic lupus erythematosus associated with Guillain-Barré syndrome with marked enhancement of nerve roots of the conus medullaris and cauda equina on MR imaging. These MR observations may help confirm the diagnosis of Guillain-Barré syndrome.