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Pediatric Diabetes 2000: 1: 88–117
Printed in Ireland. All rights reser6ed

Review

Molecular and Biochemical Analysis of the
MODY Syndromes
Winter WE. Molecular and biochemical analysis of the MODY syndromes.
Pediatric Diabetes 2000: 1: 88– 117. © Munksgaard, 2000

Abstract: Maturity onset diabetes of the young (MODY) is characterized by youth-onset diabetes that is inherited in anautosomal dominant (monogenic) pattern. Classic MODY accounts for less than 5% of
cases of childhood diabetes in Caucasians, presents prior to age 25
years, is nonketotic, and may not require insulin treatment. A variant
form of MODY that lacks a clearly defined genetic basis occurs in
African Americans [atypical diabetes mellitus (ADM)] clinically presents more acutely and is initially insulinrequiring. To date, five
molecular causes of classic MODY have been identified: hepatocyte
nuclear factor-4a (HNF-4a; MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1a (HNF-1a; MODY3), insulin promoter factor-1
(IPF-1, MODY4), and hepatocyte nuclear factor-1b (HNF-1b;
MODY5). MODY is studied as a model of beta cell hypofunction and
modest insulinopenia. Clinical recognition of ADM isimportant for
patient management to avoid confusion with type 1 diabetes mellitus.

Introduction: the definition and history of MODY
(maturity onset diabetes of the young)

An unusual form of non-insulin dependent diabetes mellitus that occurred in American youth
was first described by Dr. Stefan S. Fajans and
coworkers at the University of Michigan. As early
as 1960, these investigatorsrecognized that a form
of familial, non-obese, youth-onset diabetes existed
that was responsive to oral sulfonylurea medications (1). In 1964, Dr. Fajans coined the term
‘‘maturity-onset diabetes of the young (MODY)’’
(2). The ‘‘maturity-onset’’ portion of the term referred to the non-insulin-dependent course of the
disease characteristic of what is now classified as
type 2 diabetes (3).
The modeof inheritance of MODY was identified in the mid-1970s. In 1974, Tattersall first
described 3 MODY families with autosomal dominant inheritance (4). In 1975, 26 MODY families
with dominant inheritance were reported by Tattersall and Fajans confirming single-gene (monogenic), generation to generation inheritance of this
88

William E. Winter
University of Florida, College of Medicine.Department of Pathology, Immunology, and
Laboratory Medicine, Box 100275,
Gainesville, FL 32610-0275, USA
Key words: atypical diabetes mellitus –
glucokinase – hepatocyte nuclear factors –
maturity-onset diabetes of the young –
transcription factors
Corresponding author: William E. Winter,
M.D., University of Florida, College of
Medicine. Department of Pathology, Immunology, and LaboratoryMedicine, Box
100275, Gainesville, FL 32610-0275, USA.
Tel: + 352-392-4495; fax: + 352-8462149; e-mail: winter@pathology.ufl.edu
Submitted 8 October 1999. Accepted for
publication 16 March 2000

novel form of diabetes (5). Three or more affected
generations was not an uncommon finding in
MODY pedigrees.
Diagnostic classification of MODY syndromes

Classic MODY as first described in Caucasians byFajans and colleagues is characterized by: 1) age at
onset B 25 years old, 2) correction of fasting hyperglycemia without insulin for at least 2 years
following diagnosis, 3) nonketotic disease, and 4)
autosomal dominant mode of inheritance (6). This
form of MODY is slowly progressive, mild or
asymptomatic, and is usually noninsulin-requiring
initially after diagnosis. Because clinicalsymptoms
may be mild or absent, classic MODY is frequently
diagnosed only after performing an oral glucose
tolerance test. In some Caucasian MODY patients,
sulfonylureas have been able to correct glucose
intolerance and fasting hyperglycemia for periods
as long as 40 years (6).
The largest classic MODY pedigree studied to
date is the RW family (6). This 7 generation pedi-

The MODY...