Heterozygous cystinuria and urinary lithiasis

Giugliani, Roberto; Ferrari, Íris; Greene, Lewis Joel; Opitz, John M.; Reynolds, James F.

doi:10.1002/ajmg.1320220407

Cited by 16 publications

(5 citation statements)

References 38 publications

(9 reference statements)

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“…Oligosymptomatic individuals are also encountered among carriers of cystinuria type 1 and type 2 (MIM #104614 and MIM #604144). They can form renal stones; therefore, measuring renal cystine excretion in relatives of cystinuric patients is useful for identifying heterozygous individuals at risk [ 29 ]. Several case reports have also been published on symptomatic heterozygotes in neurological diseases, such as hereditary aceruloplasminemia [ 30 ], cerebral vessel disease [ 31 ], and α sarcoglycanopathy [ 11 ], although a full diagnostic workup was not applied and the patients underwent Sanger sequencing or WES, so the presence of the second variant remains the most probable hypothesis.…”

Section: Disease Spectrum and Phenotypic Variabilitymentioning

confidence: 99%

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Kalyta,

Stelmaszczyk,

Szczęśniak

et al. 2023

Genes

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Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur “later in life”. The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.

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Section: Disease Spectrum and Phenotypic Variabilitymentioning

confidence: 99%

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Kalyta,

Stelmaszczyk,

Szczęśniak

et al. 2023

Genes

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“…It is known that carriers of cystinuria (McKusick 220100) type II and III can form renal stones (Giugliani et al 1985). It is therefore useful to measure the renal cystine excretion in relatives of cystinuric patients to identify heterozygous individuals at risk.…”

Section: Disorders Independent Of Food Intakementioning

confidence: 99%

“…Individuals heterozygous for cystinuria should avoid episodes of extreme dehydration. Giugliani et al (1985) even believe that 'urine dilution therapy .. may play a role in the prevention of urinary stone formation in detectable cystinuria heterozygotes'.…”

Section: Preventive Aspectsmentioning

confidence: 99%

Inherited metabolic diseases affecting the carrier

Endres

1997

J of Inher Metab Disea

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The objective of this review is to draw attention to those inherited metabolic traits which are potentially harmful also for the carrier, and to outline preventive measures, at least for obligate heterozygotes, i.e. parents of homozygous children. Concerning carriers of food-dependent abnormalities, early vascular disease in homocystinuria, hyperammonaemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosaemia as well as galactokinase deficiency, spastic paraparesis in X-linked adrenoleukodystrophy, and HELLP syndrome in mothers of babies with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have to be mentioned. In the group of food-independent disorders, clinical features in carriers may be paraesthesias and corneal dystrophy in Fabry disease, lens clouding in Lowe syndrome, lung and/or liver diseases in alpha 1-antitrypsin deficiency, and renal stones in cystinuria type II and III. Finally, two monogenic carrier states are known which in pregnant individuals could possibly afflict the developing fetus, i.e. heterozygosity for galactosaemia and for phenylketonuria. Elevated levels of galactose-1-phosphate have been found in red blood cells of infants heterozygous for galactosaemia born to heterozygous mothers. Aspartame in very high doses is reported to increase blood phenylalanine levels in heterozygotes for phenylketonuria, thus being a risk for the fetus of a heterozygous mother. For some of these carrier states preventive measures can be recommended, e.g. restriction of lactose in parents and heterozygous grandparents of children with galactosaemia and galactokinase deficiency as well as transiently in infants heterozygous for galactosaemia, dietary supplementation with monounsaturated fatty acids in symptomatic carriers for X-linked adrenoleukodystrophy, avoidance of smoking and alcohol in heterozygotes for alpha 1-antitrypsin deficiency, avoidance of episodes of dehydration in heterozygotes for cystinuria, and restriction of aspartame in pregnant women.

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“…The completely recessive or type I form is twice as common in England and five times as common in Sweden [133] as type II and II combined. Type I accounts for approximately one half of cases reported in the United States.…”

Section: Cystinuriamentioning

confidence: 99%

“…Further metabolic evaluation disclosed hypercalciuria and/or hyperuricosuria in 50% . Gugliano [133] screened 200 stone patients from Brazil and detected one type I homozygote and six heterozygotes. The heterozygous gene frequency in stone populations is estimated to be between 0.04 and 0.13 [132][133][134][135], whereas the gene frequency in control populations is 0.001 to 0.009 [133].…”

Section: Cystinuriamentioning

confidence: 99%