Newborn screening (NBS) for a wide variety of inborn errors of metabolism using the powerful tool of tandem mass spectrometry (MS/MS) is becoming widespread. This article provides the basic information that primary care clinicians need to help make rational decisions about urgent evaluation and appropriate follow-up of patients with abnormal expanded NBS tests. Also outlined are ways that the screening tests can be inaccurate. A normal MS/MS NBS result does not rule out the possibility of an inborn error of metabolism in an infant with acute illness, developmental abnormalities,or other clinically suggestive conditions. Primary care practitioners should identify the metabolic specialists in their area and develop a relationship with them to ensure clear communication when abnormal results arrive. Included in this article is a catalog of "thumbnail sketches" for reference by physicians when they receive an abnormal MS/MS NBS result.

Medium-chain acyl-CoA dehydrogenase (MCAD) is a homotetrameric flavoprotein which catalyses the initial step of the beta-oxidation of medium-chain fatty acids. Mutations in MCAD may cause disease in humans. A Y42H mutation is frequently found in babies identified by newborn screening with MS/MS, yet there are no reports of patients presenting clinically with this mutation. As a basis for judging its potential consequences we have examined the protein phenotype of the Y42H mutation and the common disease-associated K304E mutation. Our studies of the intracellular biogenesis of the variant proteins at different temperatures in isolated mitochondria after in vitro translation, together with studies of cultured patient cells, indicated that steady-state levels of the Y42H variant in comparison to wild-type were decreased at higher temperature though to a lesser extent than for the K304E variant. To distinguish between effects of temperature on folding/assembly and the stability of the native enzyme, the thermal stability of the variant proteins was studied after expression and purification by dye affinity chromatography. This showed that, compared with the wild-type enzyme, the thermostability of the Y42H variant was decreased, but not to the same degree as that of the K304E variant. Substrate binding, interaction with the natural electron acceptor, and the binding of the prosthetic group, FAD, were only slightly affected by the Y42H mutation. Our study suggests that Y42H is a temperature sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures.

Our aim was to determine if the high frequency of metachromatic leukodystrophy (MLD) in Navajo Indians of the Southwestern United States is the result of a "genetic bottleneck" that occurred in the mid 19th century. Navajo Nation, Indian Health Service, and other national databases were queried for Native American patients with MLD. Pedigrees, including birth location, were established by interviewing relatives. We found that cases of MLD and their ancestors are clustered in a portion of the western Navajo Nation to which a small number of Navajo fled after armed conflict with the United States Army in the 1860s. The observed incidence of MLD on the western Navajo Nation is 1/2,520 live births, with an estimated carrier frequency of 1/25 to 1/50. No cases were observed in the eastern part of the Navajo Nation over a period of 18 years (60,000 births). The high incidence of MLD in the western Navajo Nation appears to be the result of a genetic bottleneck and probable founder effect from the mid 19th century: This mechanism may also explain the high incidence of a number of other unique, heritable disorders among the Navajo. The history of the Navajo may also be relevant to other American Indian and Alaskan Native groups that have undergone severe population reduction since the arrival of Europeans in North America.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial beta-oxidation defect, and it is potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985A-->G, and a further 18% have this mutation in only one disease allele. In addition, a large number of rare disease-causing mutations have been identified and characterized. There is no clear genotype-phenotype correlation. High 985A-->G carrier frequencies in populations of European descent and the usual avoidance of recurrent disease episodes by patients diagnosed with MCAD deficiency who comply with a simple dietary treatment suggest that MCAD deficiency is a candidate in prospective screening of newborns. Therefore, several such screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are currently used worldwide. No validation of this method by mutation analysis has yet been reported. We investigated for MCAD mutations in newborns from US populations who had been identified by prospective MS/MS-based screening of 930,078 blood spots. An MCAD-deficiency frequency of 1/15,001 was observed. Our mutation analysis shows that the MS/MS-based method is excellent for detection of MCAD deficiency but that the frequency of the 985A-->G mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. Our identification of a new mutation, 199T-->C, which has never been observed in patients with clinically manifested disease but was present in a large proportion of the acylcarnitine-positive samples, may explain this skewed ratio. Overexpression experiments showed that this is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. A carrier frequency of 1/500 in the general population makes the 199T-->C mutation one of the three most prevalent mutations in the enzymes of fatty-acid oxidation.

We recently evaluated a mentally retarded 48 year old man found to have a cytogenetic deletion of chromosome 10 [46,XY,del(10) (q25.1q25.3)]. Of interest, he shares many clinical findings with those described in Coffin-Lowry syndrome (CLS). These include severe mental retardation, short stature and a coarse facial appearance with widely spaced eyes, and patulous lips. He also had an extra transverse hypothenar crease, a finding that is seen in CLS. Furthermore, he has characteristic radiographic hand findings described in 95% of patients with CLS. The CLS gene, located at Xp22.2, has recently been identified, and mutations in the Rsk-2 gene have been identified in several CLS patients. Rsk2 is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein (MAP) kinase cascade. None of the currently recognized components of this pathway maps to the region deleted in our patient, nor are we able to identify any likely candidate genes in the deleted region, although several G protein coupled receptors have been cloned from the region. This patient's findings have some overlap with those seen in CLS, suggesting that a gene involved in MAP kinase signaling may be present in the deleted region of chromosome 10q25.1-25.3. Patients with a phenotype consistent with CLS, but lacking a family history suggestive of an X-linked disorder, should be evaluated with chromosome analysis paying particular attention to the region 10q25. Am. J. Med. Genet. 95:93–98, 2000. © 2000 Wiley-Liss, Inc.

BACKGROUND Chromosome 22q11 deletion (del22q11), the most common microdeletion syndrome, causes a wide spectrum of clinical disorders. Recent studies have suggested that significant psychiatric and behavioral disturbances occur in up to 60% of these individuals. OBJECTIVE To illustrate the spectrum of behavioral and psychiatric abnormalities associated with del22q11 and the subtle nature of its associated physical findings. PATIENTS AND METHODS Case series describing psychiatric and behavioral findings in 3 patients with del22q11. RESULTS AND CONCLUSIONS Behavioral and psychiatric problems are common in patients with del22q11 syndrome. Because the physical manifestations of the disorder are so variable and may be subtle, the behavioral and psychiatric manifestations may be the presenting problem. Providers must therefore consider del22q11 as a potential diagnosis in children and adults with behavioral and psychiatric problems. Furthermore, behavioral and psychiatric problems need to be looked for when caring for children and adolescents with a known diagnosis of del22q11.

Oculocerebrocutaneous syndrome (OCCS), or Delleman syndrome, is a multiple congenital anomaly syndrome characterized by orbital cysts, cerebral malformations, and focal dermal hypoplasia [Delleman and Oorthuys, 1981, Clin Genet 19:191-198; Delleman et al., 1984, Clin Genet 25:470-472]. Two previous reports presented children having what is suggested as the more severe form of the OCCS syndrome who also had anophthalmia, congenital hydrocephalus, and cleft lip and palate [Leichtman et al., 1994, Am J Med Genet 50:39-41; Angle and Hersh, 1997, Am J Med Genet 68:39-42]. We report on a third case of severe OCCS, an infant girl with a similar constellation of findings and additional anomalies including lateral facial cleft, vertebral anomaly, and ventricular septal defect. The additional findings in our patient highlight the phenotypic overlap of OCCS and the Goldenhar anomaly, an overlap previously noted by Delleman and Oorthuys [1981], and others [Al-Gazali et al., 1988, J Med Genet 25: 773-778]. We suggest that the minimal diagnostic criteria for Delleman syndrome include central nervous system cyst or hydrocephalus, orbital cysts or microphthalmia, and focal skin defects.