Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment

Catia Cavicchi, Maria Alice Donati, Rossella Parini, Miriam Rigoldi, Mauro Bernardi, Francesca Orfei, Nicolò Gentiloni Silveri, Aniello Colasante, Silvia Funghini, Serena Catarzi, Elisabetta Pasquini, Giancarlo La Marca, Sean David Mooney, Renzo Guerrini, Amelia Morrone

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. Methods. We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. Results: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. Conclusions: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.

Original languageEnglish
Article number105
JournalOrphanet Journal of Rare Diseases
Volume9
Issue number1
DOIs
Publication statusPublished - Jul 16 2014

Fingerprint

Ornithine Carbamoyltransferase Deficiency Disease
Brain Diseases
Early Diagnosis
Mutation
Genes
Hospital Emergency Service
Therapeutics
Hyperammonemia
Medical Staff
Fertilization in Vitro
Nervous System Diseases
Computer Simulation
Statistical Factor Analysis
Differential Diagnosis
Steroids
Hormones
Diet
Drug Therapy
Mortality

Keywords

  • Environmental triggering factors for hyperammonemia
  • Hyperammonemic encephalopathy
  • Late onset OTCD
  • Ornithine transcarbamylase deficiency (OTCD)
  • OTC gene mutations
  • Urea Cycle Disorders (UCD)

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. / Cavicchi, Catia; Donati, Maria Alice; Parini, Rossella; Rigoldi, Miriam; Bernardi, Mauro; Orfei, Francesca; Gentiloni Silveri, Nicolò; Colasante, Aniello; Funghini, Silvia; Catarzi, Serena; Pasquini, Elisabetta; La Marca, Giancarlo; Mooney, Sean David; Guerrini, Renzo; Morrone, Amelia.

In: Orphanet Journal of Rare Diseases, Vol. 9, No. 1, 105, 16.07.2014.

Research output: Contribution to journalArticle

Cavicchi, C, Donati, MA, Parini, R, Rigoldi, M, Bernardi, M, Orfei, F, Gentiloni Silveri, N, Colasante, A, Funghini, S, Catarzi, S, Pasquini, E, La Marca, G, Mooney, SD, Guerrini, R & Morrone, A 2014, 'Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment', Orphanet Journal of Rare Diseases, vol. 9, no. 1, 105. https://doi.org/10.1186/s13023-014-0105-9
Cavicchi, Catia ; Donati, Maria Alice ; Parini, Rossella ; Rigoldi, Miriam ; Bernardi, Mauro ; Orfei, Francesca ; Gentiloni Silveri, Nicolò ; Colasante, Aniello ; Funghini, Silvia ; Catarzi, Serena ; Pasquini, Elisabetta ; La Marca, Giancarlo ; Mooney, Sean David ; Guerrini, Renzo ; Morrone, Amelia. / Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. In: Orphanet Journal of Rare Diseases. 2014 ; Vol. 9, No. 1.
@article{d1fd3bbb53074051819f04dcc8a55926,
title = "Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment",
abstract = "Background: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. Methods. We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. Results: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. Conclusions: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.",
keywords = "Environmental triggering factors for hyperammonemia, Hyperammonemic encephalopathy, Late onset OTCD, Ornithine transcarbamylase deficiency (OTCD), OTC gene mutations, Urea Cycle Disorders (UCD)",
author = "Catia Cavicchi and Donati, {Maria Alice} and Rossella Parini and Miriam Rigoldi and Mauro Bernardi and Francesca Orfei and {Gentiloni Silveri}, Nicol{\`o} and Aniello Colasante and Silvia Funghini and Serena Catarzi and Elisabetta Pasquini and {La Marca}, Giancarlo and Mooney, {Sean David} and Renzo Guerrini and Amelia Morrone",
year = "2014",
month = "7",
day = "16",
doi = "10.1186/s13023-014-0105-9",
language = "English",
volume = "9",
journal = "Orphanet Journal of Rare Diseases",
issn = "1750-1172",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment

AU - Cavicchi, Catia

AU - Donati, Maria Alice

AU - Parini, Rossella

AU - Rigoldi, Miriam

AU - Bernardi, Mauro

AU - Orfei, Francesca

AU - Gentiloni Silveri, Nicolò

AU - Colasante, Aniello

AU - Funghini, Silvia

AU - Catarzi, Serena

AU - Pasquini, Elisabetta

AU - La Marca, Giancarlo

AU - Mooney, Sean David

AU - Guerrini, Renzo

AU - Morrone, Amelia

PY - 2014/7/16

Y1 - 2014/7/16

N2 - Background: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. Methods. We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. Results: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. Conclusions: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.

AB - Background: X-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations. Methods. We carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations. Results: We identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization. Conclusions: This report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.

KW - Environmental triggering factors for hyperammonemia

KW - Hyperammonemic encephalopathy

KW - Late onset OTCD

KW - Ornithine transcarbamylase deficiency (OTCD)

KW - OTC gene mutations

KW - Urea Cycle Disorders (UCD)

UR - http://www.scopus.com/inward/record.url?scp=84905277165&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905277165&partnerID=8YFLogxK

U2 - 10.1186/s13023-014-0105-9

DO - 10.1186/s13023-014-0105-9

M3 - Article

C2 - 25026867

AN - SCOPUS:84905277165

VL - 9

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

SN - 1750-1172

IS - 1

M1 - 105

ER -