The diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) can be made based on historical features. The correct diagnosis has implications for treatment and prognosis, and the diagnostic scheme may allow better focus in the search for the PKD gene(s).

Summary Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC) is an episodic movement disorder with autosomal dominant inheritance and high penetrance, but the causative gene is unknown. We have now identified four truncating mutations involving the PRRT2 gene in the vast majority (24/25) of well characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. The PRRT2 gene encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture and mutants associated with PKD/IC lead to dramatically reduced PRRT2 protein levels leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

Alx4 is a paired class homeodomain protein involved in defining anterior/posterior polarity in the developing limb bud. The paired class of homeodomain proteins cooperatively bind palindromic DNA elements as homodimers or as heterodimers with other paired homeodomain proteins. Previous characterization demonstrates that the strength of the cooperativity as well as the preference for targets is dictated largely by the identity of amino acid 50 of the homeodomain. Here we compare and contrast the DNA binding properties of a glutamine 50 paired homeodomain protein, Alx4, and a lysine 50 paired homeodomain protein, Goosecoid. We demonstrate that Alx4 homodimers, Gsc homodimers, and Alx4/Gsc heterodimers each have distinct DNA binding properties, and each can discriminate between highly related palindromic elements. Using reporter gene assays, we show that Alx4 activates transcription in a site-specific manner, and that Gsc is capable of antagonizing Alx4-mediated activation only from promoter elements that support heterodimer formation. These data demonstrate that paired homeodomain proteins with different DNA binding properties are able to form heterodimeric complexes with unique DNA binding and transcriptional activities. Thus, heterodimerization regulates the DNA binding specificity of these transcription factors and may partially explain how paired homeodomain proteins direct specific developmental functions.

OBJECTIVE To document clinicopathologic findings in domestic rabbits with liver lobe torsion and identify prognostic factors. ANIMALS 82 rabbits. PROCEDURE Medical records of 4 institutions were reviewed to identify rabbits with an antemortem diagnosis of liver lobe torsion that were examined between 2010 and 2020. RESULTS The prevalence of liver lobe torsion was 0.7% (82/11,402). In all 82 rabbits, the diagnosis was made by means of abdominal ultrasonography. Fifty (60.1%) rabbits underwent liver lobectomy, 23 (28%) received medical treatment alone, and 9 (10.9%) were euthanized or died on presentation. Overall, 32 (39%) rabbits died within 7 days of initial presentation and 50 (61%) survived. Seven-day survival rate did not differ significantly between medical treatment alone and surgical treatment. However, median survival time following medical treatment (530 days) was shorter than that following surgical treatment (1,452 days). Six of 14 rabbits had evidence of systemic inflammatory disease on necropsy. Rabbits with right liver lobe torsion were less likely to survive for 7 days than were those with caudate torsions (P = 0.046; OR, 3.27; 95% CI, 1.04 to 11.3). Rabbits with moderate to severe anemia were less likely to survive for 7 days than were rabbits that were not anemic or had mild anemia (P = 0.006; OR, 4.41; 95% CI, 1.55 to 12.51). Other factors associated with a decreased 7-day survival rate were high heart rate at admission (P = 0.013) and additional days without defecation after admission (P < 0.001). Use of tramadol was associated with an increased survival rate (P = 0.018). CLINICAL RELEVANCE The prognosis for rabbits with liver lobe torsions was more guarded than previously described. Rabbits that underwent liver lobectomy had a longer median survival time than did rabbits that only received medical treatment.

Micheli and associates [l) in a recent report in Annals described a patient with basal ganglia calcification and sporadic paroxysmal dystonic choreoathetosis without hypoparathyroidism. In a Letter to the Editor, Yamamoto and Kawazawa [ 2 ] pointed out that they had previously reported a similar case but with hypocalcemia.We are aware of an earlier report on idiopathic hypoparathyroidism [ 3 ] in a 13-year-old boy with curious attacks while playing football. He was found to have low serum calcium levels, and on skull roentgenogram "patchy cerebral calcification" was observed "situated in the region of the basal ganglia." By description his attacks were not ictal phenomena per se but episodes of dystonia with risus sardonicus. Several years ago we saw a 12-year-old boy with dizzy spells. These occurred upon standing up or upon initiation of movement such as beginning to run or walk rapidly. His mother had witnessed several episodes; she said he developed a strange smile on his face after which the right hand and arm drew up slowl!~ in the flexed position, and he bowed his head. Episodes lasted 15 to 30 seconds and could occur up to 20 times a day. O n neurological examination there were no abnormalities. When the patient was asked to sit for a minute and then suddenly stand up and walk about the chair in a clockwise ciirection, an attack was precipitated. There was no overt loss of consciousness. An electroencephalogram in the waking state revealed normal background activity with occasional low voltage spike and spike-slow wave complexes emanating from the right frontal region. The diagnosis of "reflex movement epilepsy" was made and phenytoin was prescribed. The frequency of episodes decreased dramatically. After several weeks, he developed massive myoclonic spasms of the legs that would throw him to the ground without loss of consciousness. Because of this "atypical response," a workup was undertaken and it was found that his serum calcium level was 5.6 and his serum phosphorus 11.0 mg/dl. The computed tomographic scan (Fig) revealed bilateral calcification of the basal ganglia and calcification of both frontal regions and the right cerebellar hemisphere.Ergocalciferol, 25,000 units twice a day, calcium lactate, and basal jel were prescribed. Serum calcium concentration increased to 7.4 mg/dl and all attacks ceased. Six months later he was doing well.It is likely that the enigmatic condition of "sporadic paroxysmal dystonic c:noreoathetosis" in association with hypocalcemia, hypoparathyroidism, and basal ganglia calcification represents a distinct syndrome. It should be distinguished from familial paroxysmal choreoathetosis originally

Alx4 and Cart1 are closely related members of the family of transcription factors that contain the paired-type homeodomain. In contrast to other types of homeodomains, the paired-type homeodomain has been shown to mediate high-affinity sequence-specific DNA binding to palindromic elements as either homodimers or as heterodimers with other family members. Alx4 and Cart1 are co-expressed at several sites during development, including the craniofacial mesenchyme, the mesenchymal derivatives of neural crest cells in the first branchial arch and the limb bud mesenchyme. Because of the molecular similarity and overlapping expression pattern, we have analyzed the functional and genetic relationships between Alx4 and Cart1. The two proteins have similar DNA-binding activity in vitro and can form DNA-binding heterodimers; furthermore, they activate transcription of reporter genes that contain high-affinity DNA-binding sites in cell culture in a similar manner. Therefore, at least by these criteria, the two proteins are functionally redundant. Analysis of double mutant animals reveals several genetic interactions. First, mutation of Cart1 exacerbates Alx4-dependent polydactyly in a manner that is dependent on gene dosage. Second, there are complex genetic interactions in the craniofacial region that reveal a role for both genes in the fusion of the nasal cartilages and proper patterning of the mandible, as well as other craniofacial structures. Third, double mutant mice show a split sternum that is not detected in mice with any other genotype. Interpreted in the context of the biochemical characterization, the genetic analysis suggests that Alx4 and Cart1 are indeed functionally redundant, and reveal both unique and redundant functions for these genes in development.

Mutations that affect vertebrate limb development provide insight into pattern formation, evolutionary biology and human birth defects. Patterning of the limb axes depends on several interacting signaling centers; one of these, the zone of polarizing activity (ZPA), comprises a group of mesenchymal cells along the posterior aspect of the limb bud that express sonic hedgehog (Shh) and plays a key role in patterning the anterior-posterior (AP) axis. The mechanisms by which the ZPA and Shh expression are confined to the posterior aspect of the limb bud mesenchyme are not well understood. The polydactylous mouse mutant Strong's luxoid (lst) exhibits an ectopic anterior ZPA and expression of Shh that results in the formation of extra anterior digits. Here we describe a new chlorambucil-induced deletion allele, lstAlb, that uncovers the lst locus. Integration of the lst genetic and physical maps suggested the mouse Aristaless-like4 (Alx4) gene, which encodes a paired-type homeodomain protein that plays a role in limb patterning, as a strong molecular candidate for the Strong's luxoid gene. In genetic crosses, the three lst mutant alleles fail to complement an Alx4 gene-targeted allele. Molecular and biochemical characterization of the three lst alleles reveal mutations of the Alx4 gene that result in loss of function. Alx4 haploinsufficiency and the importance of strain-specific modifiers leading to polydactyly are indicative of a critical threshold requirement for Alx4 in a genetic program operating to restrict polarizing activity and Shh expression in the anterior mesenchyme of the limb bud, and suggest that mutations in Alx4 may also underlie human polydactyly.

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