Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). If untreated by dietary restriction of phenylalanine intake, impaired postnatal cognitive development results from the neurotoxic effects of excessive phenylalanine (Phe). Signs and symptoms include severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly. Maternal PKU syndrome refers to fetal damage resulting in congenital abnormalities when the mother has untreated PKU during pregnancy. Here, we report an intellectually normal 32-year-old female who presented with recurrent pregnancy loss and two neonatal deaths with congenital heart disease, microcephaly, intrauterine growth restriction, and respiratory distress. She was diagnosed with PKU through exome sequencing performed for carrier testing with a homozygous pathogenic variant in the PAH gene, c.169_171del, p.(Glu57del) that is associated with classical PKU. Consistent with the genetic finding, she had a markedly increased plasma phenylalanine concentration of 1642 µmol/L (normal <100). This case demonstrates that recurrent pregnancy loss due to untreated maternal PKU may present as an initial finding in otherwise unsuspected classical PKU and illustrates that extreme degrees of variable expressivity may occur in classical PKU. Moreover, this case illustrates the value of genomic sequencing of women who experience recurrent pregnancy loss or neonatal anomalies.

Molecular autopsy by proxy in preconception counseling.

Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X-linked conditions. This couple-based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.

The impact of fetal middle cerebral artery Doppler on the outcome of congenital hydrocephalus.

OBJECTIVES: The objective of this study is to investigate the impact of abnormal middle cerebral artery (MCA) Doppler on the perinatal mortality in fetuses with congenital hydrocephalus (CH). METHODS: A prospective study of all fetuses with CH who delivered at our hospital over a period of 7 years. Data were obtained from the ultrasound, Labor room and intensive neonatal care unit (NICU) database. The Perinatal mortality rates were evaluated in relation to the following measures, associated congenital anomalies, cortical mantle thickness (CMT), and MCA Doppler abnormalities (absent or reversed diastole). The main outcome measure was perinatal mortality rate in relation to MCA Doppler changes. RESULTS: A total of 85 cases of CH were diagnosed and managed. The birth prevalence of CH was 2.44 per 1000 live births. On one hand, the perinatal mortality rate was higher in those fetuses with non-isolated hydrocephalus, (37.25% (19/51) versus (35.29% (12/34, p = 0.854 and in those cases with CMT <10 mm, 38.78% (19/49) versus 33.33% (12/36) in those with CMT >10 mm, p = 0.607. On the other hand, the perinatal mortality rate was significantly higher in those fetuses with abnormal MCA Doppler, (100% (13/13) versus 25% (18/72), OR = 78.0, 95% CI (5.52-44085124.60), p < 0.001. CONCLUSIONS: Abnormal fetal MCA Doppler (absent or reversed diastole) appears to be a poor prognostic indicator with significantly high perinatal mortality in fetuses with CH.

The genetic landscape of familial congenital hydrocephalus.

OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.