Many pitfalls in diagnosis of acute intermittent porphyria: a case report.

BACKGROUND: Acute intermittent porphyria is a rare autosomal dominant disorder caused by a deficiency of the enzyme, hydroxymethylbilane synthase. Recognition of acute neurovisceral attacks can be difficult due to the nonspecific nature of symptoms. CASE PRESENTATION: We report a case of 33-year-old male patient who presented with recurrent episodes of severe abdominal pain, nausea, vomiting, constipation and numbness of bilateral lower limb extremities. These nonspecific neurovisceral attacks were subject to medical and surgical misdiagnoses of acute appendicitis, sinus tachycardia, renal calculi, drug-induced acute interstitial nephritis and two episodes of partial intestinal obstruction. The sixth acute attack raised the suspicion of an acute porphyria. Watson and Schwartz test was positive for porphobilinogen in urine. Mutation analysis by DNA sequencing of the extracted DNA of the proband revealed a previously reported missense mutation, c.517C>T encoding p.R173W in the HMBS gene, confirming the diagnosis of Acute Intermittent Porphyria. Four out of five family members who underwent targeted mutation analyses were mutation-positive. CONCLUSION: The most common clinical presentation of Acute Intermittent Porphyria is abdominal pain with neurovisceral manifestations which are common to several medical, psychiatric and surgical pathologies. This leads to underdiagnosis and misdiagnosis of this disorder, incorrect management, and severe complications. Therefore, a high index of suspicion and awareness of front line laboratory investigations are important for diagnosis. Definitive diagnosis enables implementation of strategies to prevent acute attacks, and also triggers genetic testing and genetic counseling of at-risk family members.

Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population.

SUMMARY BACKGROUND: Gene-based warfarin dosing algorithms have largely been developed in homogeneous populations, and their generalizability has not been established. OBJECTIVES: We sought to assess the performance of published algorithms in a racially diverse and multiethnic sample, and determine if additional clinical variables or genetic variants associated with dose could enhance algorithm performance. PATIENTS AND METHODS: In 145 compliant patients on warfarin with a goal international normalized ratio (INR) of 2-3, stable, therapeutic doses were compared with predicted doses using 12 reported algorithms that incorporated CYP2C9 and VKORC1 variants. Additional covariates tested with each model included race, concurrent medications, medications known to interact with warfarin and previously described CYP4F2, CALU and GGCX variants. RESULTS: The mean patient age was 67 +/- 14 years; 90 (62%) were male. Eighty-two (57%) were Caucasian, 28 (19%) African-American, 20 (14%) Hispanic and 15 (10%) Asian. The median warfarin dose was 35 mg per week (interquartile range 23-53 mg per week). Gene-based dosing algorithms explained 37-55% of the variation in warfarin dose requirements. Neither the addition of race, number of concurrent medications nor the number of concurrent medications interacting with warfarin enhanced algorithm performance. Similarly, consideration of CYP4F2, CALU or GGCX variant genotypes did not improve algorithms. CONCLUSIONS: Existing gene-based dosing algorithms explained between approximately one-third and one-half of the variability in warfarin dose requirements in this racially and ethnically diverse cohort. Additional clinical and recently described genetic variants associated with warfarin dose did not enhance prediction in our patient population.

Phenotypic features of myoclonus-dystonia in three kindreds.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the epsilon-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2)gene (one family). OBJECTIVE: To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. METHODS: Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. RESULTS: Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. CONCLUSIONS: Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.

Clinical findings of a myoclonus-dystonia family with two distinct mutations.

Myoclonus-dystonia has recently been associated with mutations in the epsilon-sarcoglycan gene (SCGE) on 7q21. Previously, the authors reported a patient with myoclonus-dystonia and an 18-bp deletion in the DYT1 gene on 9q34. The authors have now re-evaluated the patient harboring this deletion for mutations in the SGCE gene and identified a missense change. In the current study, the authors describe the clinical details of this family carrying mutations in two different dystonia genes. Further analysis of these mutations separately and together in cell culture and in animal models should clarify their functional consequences.

Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism.

Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient with early onset dystonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.

A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

Association of a missense change in the D2 dopamine receptor with myoclonus dystonia.

Hereditary autosomal dominant myoclonus dystonia (MD) is a movement disorder characterized by involuntary lightning jerks and dystonic movements and postures alleviated by alcohol. Although various large families with MD have been described, no positive linkage has been found to a chromosomal location. We report a family with eight members with MD. Linkage analysis identified a 23-centimorgan region on chromosome 11q23 that cosegregates with the disease state (maximum multipoint logarithm of odds score = 2.96 at D11S897). This region contains an excellent candidate gene for involvement in the etiology of MD, the D2 dopamine receptor (DRD2) gene. Neurotransmission mediated by DRD2 is known to have a key role in the control of movement and also has been implicated in reward and reinforcement mechanisms and psychiatric disorders. Sequencing of the coding region of DRD2 indicated that all affected and obligate carriers were heterozygous for a Val154Ile change in exon 3 of the protein, which is highly conserved across species. This change was found neither in other unaffected members of the pedigree nor in 250 control chromosomes. Our finding provides evidence for the involvement of DRD2 in a disorder of the central nervous system and should lead to further insight into the function of the dopaminergic system in dystonia and other movement and mood disorders.