Bilateral symmetric T2 hyperintensities in the basal ganglia and brainstem are among the most important neuroimaging red flags for genetic disease. The prototypical example is Leigh syndrome (subacute necrotizing encephalopathy), caused by pathogenic variants in more than 75 genes affecting mitochondrial oxidative phosphorylation. Leigh syndrome classically shows bilateral symmetric T2 signal abnormality in the putamen, caudate, thalami, and periaqueductal gray matter, often with elevated lactate on MR spectroscopy. Neurodegeneration with brain iron accumulation (NBIA) disorders produce T2 hypointensity from iron deposition: PANK2 mutations cause the pathognomonic 'eye of the tiger' sign in the globus pallidus, while PLA2G6 and WDR45 (beta-propeller protein-associated neurodegeneration) show cerebellar atrophy with iron accumulation. Wilson disease (ATP7B) may demonstrate the 'face of the giant panda' sign on axial midbrain images, with T2 hyperintensity in the putamen and caudate from copper deposition. Glutaric aciduria type 1 (GCDH) produces a distinctive combination of wide sylvian fissures (frontotemporal hypoplasia) with acute basal ganglia necrosis during metabolic crises. Biotin-thiamine-responsive basal ganglia disease (SLC19A3) causes bilateral caudate and putaminal necrosis that is partially reversible with early biotin and thiamine supplementation, making recognition urgent. The key clinical distinction is between metabolic etiologies (often progressive, triggered by illness, with systemic metabolic abnormalities) and structural or toxic causes (acute onset, asymmetric, history of exposure or hypoxia).

The leukodystrophies are a heterogeneous group of inherited disorders primarily affecting central nervous system white matter. A systematic MRI-based approach evaluates white matter signal distribution (anterior vs. posterior predominant, periventricular vs. subcortical, confluent vs. patchy), the presence of specific ancillary features (enhancement, cysts, calcification), and MR spectroscopy findings to narrow the differential. Metachromatic leukodystrophy (ARSA deficiency) produces confluent periventricular white matter T2 hyperintensity with a characteristic 'tigroid' or 'leopard skin' pattern of sparing around perivascular spaces, reflecting preserved myelin around vessels. Krabbe disease (GALC deficiency) preferentially involves the optic radiations and corticospinal tracts, with peripheral nerve thickening and elevated CSF protein. X-linked adrenoleukodystrophy (ABCD1) classically shows posterior periventricular white matter involvement beginning at the splenium of the corpus callosum with an enhancing leading edge of active demyelination, progressing anteriorly; adrenal insufficiency may precede neurological symptoms by years. Alexander disease is caused by dominant gain-of-function variants in GFAP (glial fibrillary acidic protein) and produces frontal-predominant white matter disease with macrocephaly, periventricular rim enhancement, and basal ganglia and brainstem involvement. Vanishing white matter disease (EIF2B1-5) causes progressive white matter rarefaction that approaches CSF signal intensity on FLAIR, often with acute deterioration triggered by febrile illness or minor head trauma. Canavan disease (ASPA deficiency) is diagnosed by markedly elevated N-acetylaspartate (NAA) on MR spectroscopy, with diffuse white matter involvement and macrocephaly. MR spectroscopy is an indispensable adjunct: elevated lactate suggests mitochondrial disease, elevated NAA is pathognomonic for Canavan, and decreased NAA with elevated choline reflects active demyelination in many leukodystrophies.

Malformations of cortical development (MCD) result from disrupted neuronal proliferation, migration, or cortical organization and are among the most common structural causes of genetic epilepsy and intellectual disability. MRI pattern recognition combined with associated clinical features enables precise genotype prediction in many cases. The lissencephaly spectrum provides the clearest example of genotype-MRI correlation: LIS1 (PAFAH1B1) deletions or variants produce lissencephaly with a posterior-greater-than-anterior gradient (posterior agyria with anterior pachygyria), while DCX (doublecortin) mutations produce an anterior-greater-than-posterior gradient in males (anterior agyria) and subcortical band heterotopia ('double cortex') in heterozygous females. ARX mutations in males cause X-linked lissencephaly with abnormal genitalia (XLAG), a combination that immediately narrows the differential. Tubulinopathies (TUBA1A, TUBB2B, TUBB3) cause a spectrum from lissencephaly to polymicrogyria with associated distinctive basal ganglia and corpus callosum abnormalities. Polymicrogyria (PMG) may be genetic or acquired, but bilateral symmetric patterns strongly suggest genetic etiology: bilateral perisylvian PMG is associated with TUBB2B and GPR56 (ADGRG1), while GPR56 mutations cause a distinctive bilateral frontoparietal PMG with white matter changes and cerebellar hypoplasia. Periventricular nodular heterotopia (PNH) — gray matter nodules lining the lateral ventricles — is most commonly caused by FLNA (filamin A) loss-of-function variants in females (X-linked dominant, often lethal in males), presenting with epilepsy, normal to borderline intelligence, and cardiovascular anomalies. Autosomal recessive PNH is caused by ARFGEF2, typically with microcephaly. Focal cortical dysplasia type II, increasingly recognized as a somatic mosaicism disorder, involves the mTOR signaling pathway: germline variants in DEPDC5, NPRL2, and NPRL3 (GATOR1 complex components) cause familial focal epilepsy with variable focal cortical dysplasia, while somatic activating mutations in MTOR itself are found in resected FCD tissue.

Posterior fossa malformations and cerebellar abnormalities encompass a wide range of genetic disorders that can be systematically categorized by their MRI appearance. Joubert syndrome and related disorders (JSRD) are defined by the 'molar tooth sign' on axial MRI — a distinctive appearance created by thickened, horizontally oriented superior cerebellar peduncles with a deepened interpeduncular fossa, resulting from agenesis or severe hypoplasia of the cerebellar vermis. Joubert syndrome is a ciliopathy with extreme genetic heterogeneity: over 40 genes have been implicated, including CC2D2A, TMEM216, TMEM67, AHI1, and CPLANE1, all encoding components of the primary cilium or basal body. Clinical features beyond the molar tooth sign include hypotonia, oculomotor apraxia, episodic hyperpnea in infancy, and variable organ involvement (retinal dystrophy, nephronophthisis, hepatic fibrosis) that depends on the specific gene. Dandy-Walker malformation — characterized by cystic dilation of the fourth ventricle with hypoplasia or agenesis of the cerebellar vermis and enlarged posterior fossa — has been associated with ZIC1 and ZIC4 deletions, FOXC1, and chromosomal aneuploidies (trisomy 13, 18). Pontocerebellar hypoplasia (PCH) is a group of severe autosomal recessive disorders characterized by hypoplasia and progressive atrophy of both the pons and cerebellum: the TSEN complex genes (TSEN2, TSEN15, TSEN34, TSEN54) encoding tRNA splicing endonuclease subunits cause the most common forms (PCH2, PCH4); RARS2 mutations cause PCH6 with elevated CSF lactate; CASK mutations (X-linked) cause pontocerebellar hypoplasia with microcephaly predominantly in females. Progressive cerebellar atrophy patterns help distinguish genetic ataxias: the spinocerebellar ataxias (SCAs) show characteristic patterns — SCA1, SCA2, and SCA3 produce olivopontocerebellar atrophy, while SCA6 (CACNA1A) and SCA15/16 (ITPR1) show pure cerebellar cortical atrophy. Ataxia-telangiectasia (ATM) causes progressive cerebellar atrophy with elevated alpha-fetoprotein, oculomotor apraxia, and immunodeficiency.

Several genetic conditions produce stroke-like lesions or cerebrovascular disease that may be misdiagnosed as typical ischemic stroke if the clinician does not recognize distinguishing features. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), most commonly caused by the m.3243A>G variant in MT-TL1, produces cortical and subcortical lesions that characteristically do not conform to a single vascular territory, are often posterior-predominant (parietal and occipital lobes), may migrate or recur in different locations, and are associated with elevated lactate on MR spectroscopy and in plasma. The stroke-like episodes in MELAS result from mitochondrial angiopathy and neuronal metabolic failure rather than thrombotic or embolic vascular occlusion. Homocystinuria (CBS deficiency, autosomal recessive) causes early-onset thromboembolic events including ischemic stroke, often in adolescents or young adults, through endothelial dysfunction from elevated homocysteine. Associated features include marfanoid habitus, ectopia lentis (downward lens subluxation, unlike Marfan syndrome where it is upward), and intellectual disability. Fabry disease (GLA, X-linked) is an under-recognized cause of cryptogenic stroke in young adults: white matter lesions resembling small vessel disease, posterior circulation strokes (vertebrobasilar territory), and the pulvinar sign (T1 hyperintensity of the lateral pulvinar nuclei from dystrophic calcification) should prompt GLA enzyme activity and genetic testing. Moyamoya disease — progressive stenosis of the distal internal carotid arteries with compensatory collateral vessel formation (the 'puff of smoke' on angiography) — occurs as an isolated condition (RNF213 is the major susceptibility gene, particularly in East Asian populations) and in association with several genetic syndromes including neurofibromatosis type 1 (NF1), Down syndrome, sickle cell disease, and Turner syndrome. COL4A1 and COL4A2 mutations cause a spectrum of cerebrovascular disease from prenatal porencephaly (schizencephaly-like cavities) to adult-onset small vessel disease with lacunar infarcts, white matter changes, and intracerebral hemorrhage, often with associated ocular anomalies and renal disease. The critical clinical skill is distinguishing these genetic stroke mimics from atherosclerotic or cardioembolic stroke by recognizing the atypical age of onset, non-vascular territory distribution, associated systemic features, and family history.