Corticobasal degeneration (CBD) was first described around 50 years ago as a primary motor disorder that exhibits an asymmetric akinetic-rigid syndrome and apraxia along with characteristic pathology findings.[1, 2] Diverse clinical presentations have now been identified, and neuropathological criteria have hence been modified.[4, 5] Because the underlying pathology in patients displaying symptoms similar to CBD is heterogeneous,[6-9] the term corticobasal syndrome (CBS) was introduced for patients awaiting pathological confirmation.
In 23% to 25% of all patients, CBS is linked to Alzheimer-type pathology (CBS-AD),[11-14] and therefore represents the second-most common type of clinically diagnosed CBS. To date, it has not been possible to establish specific features that might allow a definite diagnosis of CBS-AD before pathological confirmation, despite proposals based on selected sets of clinical symptoms, neuropsychological profiles, or neuroimaging findings. In consequence, the diagnosis during the patient's lifetime remains uncertain. Tau/Abeta ratio in cerebrospinal fluid (CSF) may represent a useful way to detect CBS-AD in vivo, although neuropathological confirmation is not yet forthcoming and the technique's sensitivity for detecting CBS-AD at an early stage has yet to be determined.
CBS-AD series published to date correspond to genetically sporadic patients. We describe a Spanish family with pathologically confirmed cases of early-onset, autosomal-dominant familial Alzheimer's disease (EOFAD) linked to a Met233Leu mutation of the presenilin-1 gene (PSEN-1). Three family members carrying the mutation were examined by us, and 2 presented the amnestic form of the disease. In contrast, the third member studied presented with neuropsychiatric symptoms, a severe behavior disorder and a clear-cut CBS, as documented in Video 1, and AD was pathologically confirmed. We believe this combination of clinical and genetic features, as well as its relevance in CBS-AD diagnosis, has not been previously described.
Patients III7 and IV14 in the extended family presented here display typical findings of EOFAD linked to PSEN-1 mutations, and the disease was confirmed pathologically in 1 family member (III5). Essential features of the family consist of autosomal-dominant inheritance pattern, memory problems at presentation, and the occasional association of myoclonus, seizures, or aphasia in advances stages of the disease.[29, 30]
A Met-Leu amino acid substitution at codon 233 had been identified in early-onset forms of AD in patients from the same city as the family we describe. Although no relationship could be demonstrated between the two families, a remote common founder cannot be ruled out. The mutation was also found in a referral-based series screening for PSEN-1 mutations in early-onset AD. Interestingly, severe frontal dysfunction at presentation, similar to that in patients with CBS-AD, has been reported in 2 Met-233-Leu PSEN-1 patients with sporadic early-onset AD.[33, 34]
Some characteristics of our patient with CBS-AD, such as family history, very early disease onset, and severe neurobehavioral disorders at presentation are more in keeping with features often found in families with EOFAD and PSEN-1 mutations, whose genetics he shared, rather than the sporadic, comparatively late onset of CBS-AD cases reported to date. Familial AD secondary to PSEN-1 mutations may therefore exhibit initially psychiatric or behavioral traits,[35, 36] sometimes mimicking the behavioral variant of frontotemporal dementia,whereas myoclonus and seizures are also well known.[38-40] Some patients clinically diagnosed with CBS and showing Alzheimer-type pathology lacked the usual clinical asymmetry for motor and sensory signs,[15, 41] which has been suggested as a predictive feature of CBS-AD. In this regard, we must emphasize the marked clinical and neuroimaging asymmetry displayed by our case.
Patients clinically resembling our case III6 were reported on in 1966 by Heston et al. Those researchers presented a family of 19 patients spanning four generations with progressive dementia combined with prominent parkinsonism and pyramidal tract signs. Focal motor findings represented the first sign of neurological abnormality in 2 of the patients personally examined by the authors, manifesting as progressive clumsiness and weakness of their right hands and legs. Symptoms at onset in another patient (IV2) consisted of stiffness and tremor in the left extremities. AD was confirmed pathologically in 4 of the 19 individuals affected. Some EOFAD variants linked to PSEN-1 mutations may express early motor disturbances, such as spastic paraparesis[43, 44] or parkinsonism.[45, 46] Case III6 and those from the Heston et al. family might thus represent another motor disturbance, such as CBS related to PSEN-1 mutations.
Thus far, genetic CBS has been reported in families with autosomal-dominant frontotemporal lobar degeneration (FTLD) linked to progranulin (PGRN) gene mutations, which represent between 5% and 7.9% of all cases in large series. As in our patient III6, CBS in PGRN families may occur in young adults and neurobehavioral abnormalities may be associated at onset. FTLD may underlie a wide range of clinical presentations; in contrast, 2 of the 3 family members described here presented with a pure amnestic disorder. Mutations in the MAPT gene have been demonstrated in a sporadic case of CBD and in 2 elderly first cousins, 1 of whom had additional pathological findings consistent with AD.
Pathogenic C9orf72 repeat expansions are rarely found in patients with CBS and diverse forms of parkinsonism. A study screening 37 patients with CBS features for this gene found repeat expansions in only 3 patients. However, a positive family history of FTLD or of motor neuron disease in a CBS patient would justify screening for this mutation.As a result, we propose testing for PSEN-1, PGRN, MAPT, and C9of72 gene mutations, particularly in patients with CBS and a positive family history suggesting a neurodegenerative condition.[55, 56]
Predicting the underlying pathology in CBS-AD has proved difficult, although it might be theoretically possible in cases linked to mutations in the presenilin genes. We conclude that CBS may represent an atypical clinical presentation in autosomal-dominant EOFAD. In addition, evidence of mutations linked to the PSEN-1 gene may represent a unique opportunity to predict Alzheimer-type pathology in vivo.