A Case of DNAJC12-Deficient Hyperphenylalaninemia Detected on Newborn Screening: Clinical Outcomes from Early Detection.

DNAJC12-deficient hyperphenylalaninemia is a recently described inborn error of metabolism associated with hyperphenylalaninemia, neurotransmitter deficiency, and developmental delay caused by biallelic pathogenic variants of the DNAJC12 gene. The loss of the DNAJC12-encoded chaperone results in the destabilization of the biopterin-dependent aromatic amino acid hydroxylases, resulting in deficiencies in dopamine, norepinephrine, and serotonin. We present the case of a patient who screened positive for hyperphenylalaninemia on newborn screening and was discovered to be homozygous for a likely pathogenic variant of DNAJC12. Here, we review the management of DNAJC12-related hyperphenylalaninemia and compare our patient to other reported cases in the literature to investigate how early detection and management may impact clinical outcomes.

Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.

Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants.

PURPOSE: We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann-Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening. METHODS: At five participating high-birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome. RESULTS: Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status. CONCLUSION: Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Subspecialty evaluation of chronically ill hospitalized patients with suspected immune defects.

BACKGROUND: The diagnosis of primary immunodeficiency is suggested by recurrent or unusual infections and inflammatory and autoimmune conditions. Because the diversity of immune defects and clinical presentations poses a diagnostic challenge in hospital populations, a computer algorithm was devised to help identify patients. OBJECTIVE: To assess use of pertinent subspecialty clinics by patients with clinical features of immunodeficiency. METHODS: Using a validated algorithm based on International Classification of Diseases, Ninth Revision (ICD-9), codes applied to The Mount Sinai Hospital billing records, we investigated hospitalized patients, 60 years or younger, who had been diagnosed as having conditions associated with immunodeficiency, excluding those with confounding medical conditions. Immunodeficiency-related disease codes were given a weighted score based on relative severity and expressed as a sum for admissions between January 1, 1999, and December 31, 2003. Demographic features, subspecialty care, and clinic attendance were determined. RESULTS: The 296 computer-identified patients with illnesses characteristic of immunodeficiency were 35.8% Hispanic, 27.0% African American, and 21.6% white; their median age was 13.3 years. Patients were hospitalized 1,261 times, or a median of 4.2 times each (range, 1-42 times), and had 5,700 diagnoses. Of the patients, 75.0% received primary care at The Mount Sinai Hospital. Although the most common diagnosis was pneumonia (n = 243), 45% of patients never received allergy/immunology or pulmonary subspecialty care. CONCLUSION: Despite receiving primary medical care at the same hospital, many frequently hospitalized subjects with features of immunodeficiency do not receive medical care in appropriate subspecialty clinics.

X-linked agammaglobulinemia in a 10-year-old child: a case study.

PURPOSE: To discuss the advanced practice nurse's diagnosis and management of an unsuspected primary immunodeficiency (PI) disease, X-linked agammaglobulinemia (XLA), in a child. DATA SOURCES: Review of historical and current scientific literature, practice guidelines, and a case study. CONCLUSIONS: While a diagnosis of XLA is most commonly made in the first 3 years of life, this case study presents a 10-year-old boy's circuitous route to this diagnosis. A diagnosis of an immune defect should be considered for patients with chronic, recurrent, or unusual infections. For patients who lack immune globulins and antibodies, intravenous immune globulin, given monthly and continued throughout life, is the standard of care. IMPLICATIONS FOR PRACTICE: Diagnosis of children and adults with primary immune deficiency diseases may be delayed if practitioners fail to find the root cause of recurrent infections. Nurses as patient advocates should recognize the need for a referral in clinical cases where immunodeficiency may not be suspected. Evaluation of the immune system is performed by a panel of blood tests. There is a need to increase awareness of PI, their manifestations, and treatment among nurses both at the bedside and in advanced practice settings.

Recognizing primary immune deficiency in clinical practice.

Primary immunodeficiency results in recurrent infections, organ dysfunction, and autoimmunity. We studied 237 patients referred for suspicion of immunodeficiency, using a scoring system based on clinical information. The 113 patients with immunodeficiency had higher scores and more episodes of chronic illnesses and were more likely to have neutropenia, lymphopenia, or splenomegaly.

Identifying undiagnosed primary immunodeficiency diseases in minority subjects by using computer sorting of diagnosis codes.

BACKGROUND: Primary immunodeficiency diseases occur in all populations, but these diagnoses are rarely made in minority subjects in the United States. OBJECTIVE: We sought to develop and validate a method to identify patients without diagnoses but with immunodeficiency in an urban hospital with a substantial minority patient population. METHODS: We developed a scoring algorithm on the basis of International Classification of Disease, Ninth Revision (ICD-9) codes to identify all hospitalized patients age 60 years or less who had been given a diagnosis of 2 or more of 174 ICD-9-coded complications associated with immunodeficiency. Codes were weighted for severity and expressed as a sum for all admissions between October 1, 1995, and December 31, 2002. Patients with, for example, cancer or HIV or those after transplantation or major surgery were excluded. Demographic features of subjects with aggregated ICD-9 codes suggestive of immunodeficiency were compared with those of other inpatients; 59 computer-selected subjects were then tested for immune defects. RESULTS: The computer-identified group contained 533 patients (0.4% of all inpatients), who had been hospitalized 2683 times. The median age was 6.6 years. Sixty-five percent were African American or Hispanic, and 61% were insured by Medicaid, which is significantly more than other inpatients younger than 60 years of age (median age, 32.6 years; 37% minority, 27% insured by Medicaid; P<.0001). Primary immunodeficiency was found in 17 (29%) of the 59 subjects tested. Thirteen other patients had secondary immune defects, and 86% of immunodeficient subjects were Hispanic or African American. CONCLUSIONS: An ICD-9-based scoring algorithm identifies patients demographically different from other hospitalized subjects who have multiple illnesses suggestive of immunodeficiency. This group contains undiagnosed minority patients with immunodeficiency.