Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme with very low residual activity, or an enzyme with relatively high residual activity but still phenotypic consequences. This enzyme deficiency allows glutaric acid, 3-hydroxyglutaric acid and to a lesser extent glutaconic acid to build up to abnormal levels, especially at times when the body is under stress. These intermediate breakdown products are particularly prone to affect the basal ganglia, causing many of the signs and symptoms of GA1. GA1 occurs in approximately 1 of every 30,000 to 40,000 births. As a result of founder effect, it is much more common in the Amish community and in the Ojibway population of Canada, where up to 1 in 300 newborns may be affected. Relatives of children with GA1 can have low GCDH activity: in an early study of GA1, GCDH activity was found to be 38%, 42%, and 42% in three of the four unaffected relatives tested, a pattern consistent with the 50% level that would be expected in heterozygous carriers. Those levels are close to those found in some heavily symptomatic GA1-affected children. Diagnosis
Normally, magnetic resonance imaging shows the Sylvian fissure to be operculated, but in GA1-associated encephalopathy, operculation is absent. In many jurisdictions, GA1 is included in newborn screening panels. Elevated glutarylcarnitine can be detected by mass spectrometry in a dried blood spot collected shortly after birth. After a positive screening result, confirmatory testing is performed.
A lentigo () (plural lentigines, ) is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement membrane of the epidermis where melanocytes normally reside. This is in contrast to the "nests" of multi-layer melanocytes found in moles (melanocytic nevi). Because of this characteristic feature, the adjective "lentiginous" is used to describe other skin lesions that similarly proliferate linearly within the basal cell layer. Diagnosis
Conditions characterized by lentigines include:
Lentigo simplex
Solar lentigo (Liver spots)
PUVA lentigines
Ink spot lentigo
LEOPARD syndrome
Mucosal lentigines
Multiple lentigines syndrome
Moynahan syndrome
Generalized lentiginosis
Centrofacial lentiginosis
Carney complex
Inherited patterned lentiginosis in black persons
Partial unilateral lentiginosis
Peutz–Jeghers syndrome
Lentigo maligna
Lentigo maligna melanoma
Acral lentiginous melanoma

Differential diagnosis
Lentigines are distinguished from freckles (ephelis) based on the proliferation of melanocytes. Freckles have a relatively normal number of melanocytes but an increased amount of melanin. A lentigo has an increased number of melanocytes. Freckles will increase in number and darkness with sunlight exposure, whereas lentigines will stay stable in their color regardless of sunlight exposure. Treatment
Lentigines by themselves are benign, however one might desire the removal or treatment of some of them for cosmetic purposes. In this case they can be removed surgically, or lightened with the use of topical depigmentation agents.