Diagnosis of Inherited Metabolic Disease in Older Patients: A Systematic Literature Review

ABSTRACT

Inherited metabolic diseases (IMDs) are genetic disorders that disrupt biochemical processes in the human body, due to pathogenic variants in genes encoding enzymes or transporters. While IMDs are mostly diagnosed in infancy or childhood, there is an increasing number of diagnoses in adult patients. Delayed diagnosis, particularly in older patients, may reflect the diagnostic odyssey usually observed in rare diseases' patients and can result in complications and reduced quality of life for patients and their families. The aim of the study was to better characterize the diagnosis of IMDs in older patients (≥ 65 years). We conducted a systematic literature review (SLR) to examine the diagnosis and clinical presentation of IMDs in patients aged 65 and older. We searched databases like PubMed, Embase, and Lilacs for relevant studies from 1965 to 2023. A total of 260 articles were included, representing 293 patients with a median age of 69 years at diagnosis. From this SLR, 67 different diagnoses have been reported. The most frequently reported diseases were Fabry disease, alkaptonuria, Gaucher disease, mitochondrial disorders, and glycogen storage disease type V. Median diagnostic delay was 14.5 years with a wide range of 1–91 years. Musculoskeletal symptoms were the most frequently reported, followed by neurological and cardiovascular symptoms. Our findings underscore the importance of recognizing IMDs in older patients and the need for awareness among healthcare providers to improve diagnosis and patient care. Future guidelines and teaching programs should incorporate metabolic investigations for older patients presenting with symptoms suggestive of IMDs.

1. Introduction

Inherited metabolic diseases (IMDs) are a group of genetic disorders that disrupt complex biochemical processes of the human body. These conditions are mostly due to variants in specific genes encoding essential enzymes or transporters involved in the synthesis or catabolism of biochemical compounds [1]. The result is often a cascade of clinical symptoms that can vary widely depending on the specific error of metabolism. Symptoms of IMD may include neurological and muscular symptoms, as well as growth and developmental deficiencies, but they can impact any system or organ. Diagnosis of IMDs is more common in newborns, infants, and children, as the symptoms often manifest early in life. However, so‐called “late onset” forms of IMDs exist, and as a result, the number of adult patients diagnosed with IMD has increased over time [2]. Usually, suspicions of late onset IMD concern mostly young and middle‐aged adults. However, the probability of diagnoses in older patients should be examined. From our clinical experience, diagnosis of IMDs can be made at any age, even in patients over 80 years [3]. Indeed, an article published in 1965 documented primary oxalosis in an elderly man, highlighting that metabolic genetic disorders can also present later in life [4]. This finding expanded the understanding of IMDs and broadened the scope of clinical awareness for all age groups.

In 2016, Sirrs et al. published an international survey of adult metabolic centers, which showed that, out of approximately 2000 patients, more than 40% were diagnosed in adulthood [5]. This publication demonstrated the importance of developing the field of adult metabolic medicine. However, specific data about older adult patients remain scarce. This lack of data poses significant challenges for accurate diagnosis and effective treatment of IMD in this growing population. Delayed diagnosis of IMD in older adults can lead to complications and significantly impact their quality of life [6]. Understanding the epidemiology and clinical manifestations of IMDs in older patients appears to be crucial for optimizing patient care, raising awareness among physicians, and identifying new areas for research.

In order to get new insights about the diagnosis of IMDs in older patients, we conducted a systematic review of the literature (SLR). The primary aim of our study was to identify which IMDs have been reported in older patients, for those 65 years of age and over. The secondary aim of the study was to determine the main symptoms that lead to a diagnosis of IMD in older patients.

2. Methods

This SLR followed the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) 2020 checklist [7].

2.1. Search Strategy and Search Terms

Searches of electronic databases were carried out on 19 March 2023. Databases searched were PubMed, Embase, and Lilacs from 1965 to 2023. The following search terms were used: (“Metabolism, Inborn Errors” [Mesh] OR (Errors Metabolism, Inborn) OR (Errors Metabolisms, Inborn) OR (Inborn Errors Metabolism) OR (Inborn Errors Metabolisms) OR (Metabolisms, Inborn Errors) OR (Metabolism Errors, Inborn) OR (Error, Inborn Metabolism) OR (Errors, Inborn Metabolism) OR (Inborn Metabolism Error) OR (Inborn Metabolism Errors) OR (Metabolism Error, Inborn) OR (Inborn Errors of Metabolism) OR (Metabolism Inborn Error) OR (Metabolism Inborn Errors)) AND (“aged” [Mesh] OR (Aged, 80 and over) OR (65 over) OR (elderly) OR (Frail Elderly) OR (Centenarians) OR (Nonagenarians) OR (Octogenarians)) AND (“Diagnosis” [Mesh] OR (Diagnoses) OR (Diagnose) OR (Diagnoses and Examinations) OR (Examinations and Diagnoses) OR (Diagnoses and Examination) OR (Examination and Diagnoses) OR (Screening) OR (Detection)). The reference lists of existing reviews and identified articles were examined individually using RAYYAN software. The abstracts obtained were divided into two groups. In each group, abstracts were screened by three authors working independently and matching their results. Group 1 included MRM, YMNA and MG whereas group 2 included JCM, AMA and ES. Any disagreement was resolved by a fourth person as a judge (IVDS and FM for group 1 and 2, respectively). After the harmonization of the first selection, both groups read the full papers to select those that should be included in the SLR. The flow diagram of the study selection process is depicted in Figure 1.

FIGURE 1.

Flow diagram of the study selection process.

Inclusion criteria: (a) Age at IMD diagnosis ≥ 65 years; (b) type of study: case reports, case series, cohort studies, systematic literature reviews, screening studies; (c) language: English, Italian, French, Portuguese, Spanish, and Dutch.

Exclusion criteria: (a) Articles about diseases that did not belong to the list of the international classification of inherited metabolic disorders [1]; (b) type of study: narrative reviews, experimental studies, non‐humans; (c) “common” metabolic conditions: gout, amyloidosis, hemochromatosis, G6PD, diabetes, hyperlipidemia.

2.2. Descriptive Analysis of Patients

Diseases were counted and ranked according to the number of identified patients, from the most to the less frequently reported. A specific subgroup analysis was performed for the most frequently reported disease identified in older patients through the SLR. When the age of diagnosis and age of first symptoms were both available in selected papers, diagnostic delay was calculated. From the selected papers, symptoms and clinical signs (general, dermatological, cardiovascular, ophtalmological, neurological, musculoskeletal, bone symptoms, psychiatric, gastro‐intestinal, genito‐urinary, hematological, renal insufficiency, ontological, respiratory, dysmorphic features) as well as electrolyte disturbances and abnormality of acid–base homeostasis were tagged as “symptoms” and then were classified into categories and further ranked from 1 to 4, with 1 being the presenting symptom of the disease, followed by three other main symptoms.

2.3. Statistical Methods

Descriptive statistics were used. Quantitative variables were tested regarding the normal distribution by the Shapiro–Wilk test. Asymmetrical variables were presented as median ± interquartile range (Q1, Q3). All the statistics were performed using Statistics Kingdom online (https://www.statskingdom.com/mean‐median‐mode‐calculator.html).

3. Results

3.1. Study Selection

The initial searches identified 28 338 citations. After removing duplicates (n = 277), 28 061 potentially relevant articles were assessed using title and abstract review. A total of 428 articles were identified for full text assessment. After screening the full texts, we included 260 articles [3, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266] representing 242 case reports (CR) and case series (CS) and 18 screening studies (SS) (Figure 1).

3.2. Descriptive Analysis of Patients

From the 260 selected articles, 293 patients were identified. Patients selected from CR/CS and SS are presented in Tables S1 and S2, respectively. For the whole population, median age at diagnosis was 70 ± 7 years [67, 68, 69, 70, 71, 72, 73, 74]. The two oldest reported patients were diagnosed at the age of 92 years. One was diagnosed with Hermansky–Pudlak syndrome, and the other with Fabry disease (FD) in a selective SS of male patients with left ventricular hypertrophy. In total, 64 different diseases have been identified. FD was the most frequent disease in our study (n = 66), but 44% of these patients were diagnosed through selective SS. The second most frequently reported IMD was alkaptonuria (n = 54), followed by mitochondrial disorders (n = 21), Gaucher disease (GD; n = 17), glycogen storage disease (GSD) type V (GSD 5; n = 13), GSD type II (n = 10), hypophosphatasia (n = 7) and Wilson disease (n = 6). All the diseases identified in our SLR are presented in Table 1.

TABLE 1.

All diseases identified in the systematic review (n = 64).

Disease	n
Fabry disease	66
Alkaptonuria	54
Gaucher disease type I	17
Glycogen storage disease type V	12
Glycogen storage disease type II	10
MELAS syndrome	10
Hypophosphatasia	7
Wilson disease	6
Cerebrotendinous xanthomatosis	5
Multiple acyl‐CoA dehydrogenase deficiency	5
Tangier disease	5
Neutral lipid storage disease	4
Niemann‐Pick disease type C	4
Ornithine transcarbamylase deficiency	4
X‐linked Adrenoleukodystrophy	4
Acid sphingomyelinase deficiency type B	3
Hermansky‐Pudlak syndrome	3
Leber hereditary optic neuropathy	3
POLG related disorder	3
Polyglucosan body disease	3
Glucose transporter type I deficiency syndrome	3
Glycogen storage disease type XV	3
Acute intermittent porphyria	2
Carnitine palmitoyltransferase type II deficiency	2
Citrullinemia type II	2
Congenital adrenal hyperplasia (17α‐hydroxylase deficiency)	2
Congenital adrenal hyperplasia (21‐hydroxylase deficiency)	2
Glycogen storage disease type IX	2
Krabbe disease	2
Leigh syndrome	2
Lipoprotein lipase deficiency	2
MERFF syndrome	2
Multiple DNA mitochondrial deletions	2
Porphyria cutanea tarda	2
Primary hyperoxaluria	2
Xanthinuria type I	2
X‐linked ichthyosis	2
Aceruloplasminemia	1
Adenine phosphoribosyltransferase deficiency	1
Alexander disease	1
Carbamoylphosphate synthetase deficiency	1
Congenital bile acid synthesis defect type IV	1
Coproporphyria	1
Gitelman syndrome	1
Glycogen storage disease type III	1
Glycogen storage disease type VII	1
GM2 Gangliosidosis	1
Hereditary butyrylcholinesterase deficiency	1
Hereditary fructose intolerance	1
Hereditary renal hypouricemia type I	1
HHH syndrome	1
Hypophosphatemic rickets	1
Lecithin‐cholesterol acyltransferase deficiency	1
Lesch–Nyhan syndrome	1
Mucopolysaccharidosis type IIIa	1
Mucopolysaccharidosis type IIIb	1
Mucopolysaccharidosis type IVb	1
Polyglucosan body myopathy type II	1
Primary muscle carnitine deficiency	1
Primary trimethylaminuria	1
Respiratory chain complex I defect	1
Sandhoff disease	1
Schindler disease	1

Abbreviations: HHH syndrome = Hyperornithinemia, Hyperammonemia, and Homocitrullinuria Syndrome; MELAS = mitochondrial encephalomyopathy, lactic acidosis, stroke‐like episodes; MERRF = myoclonic epilepsy with ragged red fibers; POLG = polymerase gamma.

The age of onset of the first symptoms was below 65 years old for most of the patients, and the median diagnostic delay was calculated at 14.5 ± 22 years [5, 27]. Patients with FD are described in a subgroup analysis (see below). Considering patients not diagnosed through SS, alkaptonuria was then the most frequently reported disease in our study, which included 54 patients (27 women and 27 men). Clinical presentations of diagnosed patients not included by SS studies as well as symptoms relations are depicted as heatmaps in Figures 2 and 3, respectively. Musculoskeletal symptoms were the first symptoms most commonly reported, followed by neurological and cardiovascular symptoms. From Figure 3, the association of musculoskeletal symptoms and dermatological symptoms appeared to be the most prevalent.

FIGURE 2.

Frequency of the first, second, third and fourth symptoms reported by the patients included in the systematic review. Rank 1: First reported symptom; 2: Second reported symptom; 3: Third reported symptom; 4: Fourth reported symptom.

FIGURE 3.

Relations between the first and the second symptoms reported by the patients included in the SLR.

3.3. Subgroup of Patients With Fabry Disease

As FD was the most frequent disease identified in our SLR, we performed a subgroup analysis of these patients. Among 66 patients diagnosed with FD, 37 (56%) and 29 (44%) patients were reported in CR and SS, respectively. Female patients represented 18/37 (49%) and 15/29 (52%) patients from CR and SS, respectively. Median age at diagnosis of patients from CR and SS was 70 ± 9 [67, 76] and 74 ± 3 [72, 75] years, respectively. The clinical pictures of these both groups are described in Figure 4. Briefly, as compared to patients reported in SS, FD from CR had more general symptoms (8% vs. 0%), respiratory symptoms (8% vs. 0%), ophthalmological symptoms (19% vs. 7%) as well as musculoskeletal symptoms (11% vs. 3%).

FIGURE 4.

Clinical picture of older patients diagnosed with Fabry disease (n = 66).

4. Discussion

The present study presents novel data from a SLR about the diagnosis of IMD in elderly people, and to our knowledge, this is the first study of its kind. The main finding of this SLR is that many IMDs can be diagnosed at 65 years of age and over. Indeed, 64 different diseases have been identified, including very rare IMDs and some unexpected diseases which are usually diagnosed in newborns or young children. FD and alkaptonuria were the most frequently diagnosed diseases in our study. From this SLR, we were also able to extract data about the clinical presentations of the numerous published cases, which bring new insights about metabolic medicine in adults. Altogether, these findings underscore the importance of not limiting metabolic investigations to younger patients and draw attention to the fact that health professionals who care for adults and older patients should be able to identify the main clinical manifestations of IMDs in this population.

The other interesting finding of the study is the diagnostic delay reported in patients reported in CS/CR (not in SS). Median diagnostic delay was almost 15 years but with a wide range, from 1 to 91 years. The 91 years delay is a case of a patient with Hermansky‐Pudlak syndrome who was symptomatic since the age of 1 year with a diagnosis confirmation at the age of 92 years [166]. Besides this exceptional case, mean diagnostic delay that we observed reflects the diagnostic odyssey of patients with IMD and rare diseases in general [266]. Diagnostic delay observed in our study may correspond to several explanations. First, it reflects that IMDs in adults and older persons are still unrecognized by healthcare professionals. Second, due to their age, patients included in our study may reflect a period of time when rare diseases centers, including reference centers for IMD, were not as developed as today. Another explanation could be that affected patients may have presented mild forms of IMD due to specific genetic variants. Indeed, in some diseases, genetic variants are known to be associated with late onset forms. In FD, for example, some GLA variants have been associated with late onset forms of the disease [267, 268]. However, it is of note that late diagnosed patients do not include only cases of mild forms of IMD. As an example, our SLR has identified a patient diagnosed through family screening with a Lesch–Nyhan variant syndrome at the age of 65 years. Out of the three affected family members in this report, the oldest patient was the most severely affected [180], showing that he has been misdiagnosed for many years. One other potential explanation of some very long diagnostic delays relies on patients' adaptation to the handicap related to the underlying disease. The present SLR has included a patient that we have already reported with a very late diagnosis of GSD type 5, at the age of 82 years [3]. The story of this patient is remarkable as he has continuously adapted his personal and professional life to his muscular disability. As a result, he never complained to any doctor and was diagnosed with typical GSD type 5 in the context of the investigation of persistent elevated CK following statin withdrawal after coronary bypass surgery.

The highest number of patients diagnosed through selective SS are those affected by FD. This is not surprising as many industry‐sponsored screening studies for FD have been published to date, including patients with hypertrophic cardiomyopathy, kidney disease, or stroke. For FD patients diagnosed by screening or reported in CS/CR, cardiovascular symptoms were predominant, but some differences appeared between groups. Indeed, the analysis of symptoms in patients diagnosed with FD not by screening gives a more comprehensive picture of clinical symptoms leading to FD disease in the elderly. As such, it appears that beyond cardiovascular, renal, or neurological symptoms, older patients may present with musculoskeletal, respiratory, or general symptoms. It would be interesting to determine whether these clinical forms are related to some specific variants of FD.

From our SLR, we were able to identify the main symptoms of IMDs in older people. Our heatmap analysis of symptoms suggests that musculoskeletal symptoms are a hallmark of IMDs in older patients (Figure 2). This finding is explained by the most frequent diseases identified in our SLR, including FD, alkaptonuria, GD, mitochondrial disorders, and GSD type II, as these diseases may present with musculoskeletal symptoms. Such results suggest that clinicians should include investigation of IMDs in the diagnostic work‐up of older patients with musculoskeletal symptoms. At the second and third ranks of our heatmap, we observed neurological and cardiovascular symptoms, respectively. Such symptoms are also representative of the most frequent diseases included in the present study. Regarding our heatmap analysis of symptom relations, our main finding is that the association of musculoskeletal symptoms with dermatological symptoms could suggest an IMD. Obviously, such association corresponds to both diagnoses of FD and alkaptonuria, which strengthens the concept that these diseases should be more often investigated in older patients. Finally, our analysis does not allow us to determine whether there are some specific pictures of IMDs in older patients but raises awareness about which clinical symptoms could indicate an IMD in this group of patients.

Considering only patients reported in CR/CS, alkaptonuria was the most reported IMD in our SLR, although this is a very rare disease that affects from 1/250 000 to 1 000 000 people worldwide [269]. Alkaptonuria is due to 1,2 dioxygenase deficiency linked to HGD gene variants. This is a slowly progressive disease affecting mostly joints, spine, cardiac valves, as well as the urogenital system, due to progressive homogentisic acid deposits in the connective tissues. Ophtalmological and skin changes are also part of the clinical picture of alkaptonuria. Thus, the disease is characterized by a latency period, and the onset of symptoms is usually at 30–40 years [269] but may be later in life, as shown in our study. Whatever the age, alkaptonuria is a treatable disease that requires medications including pain killers and nitisinone, along with a low protein diet, physical therapy, and orthopedic or cardiac surgery if necessary [270]. It is of note that it has been recently shown that nitisinone improves both quality of life and function of patients with alkaptonuria [271]. From our experience, we recommend prescribing nitisinone even in older patients suffering from alkaptonuria, with a close attention to any side effects that may occur.

Beyond the most frequent diseases that were described in our results, our SLR has identified a significant number of other IMDs diagnosed in older patients. This included different forms of porphyrias, acid sphingomyelinase deficiency, urea cycle disorders, cerebrotendinous xanthomatosis (CTX), rare forms of GSDs, Hermansky‐Pudlak syndrome, hypophosphatasia, some types of mucopolysaccharidosis, multiple acyl‐CoA dehydrogenase deficiency, polyglucosan body disease, Tangier disease, X‐linked adrenoleukodystrophy, and other diseases that have been reported only once in our literature search (Table 1). Isolated cases do not necessarily mean that single reports are related to the incidence but to the natural history of diseases which commonly present with symptoms in children or young adults and not in older people. As an example, CTX, which is an autosomal recessive disorder of bile acid synthesis due to pathogenic variants in the cytochrome P450 CYP27A1 gene, has a slowly progressive course in which symptom onset varies from childhood to late adulthood [272] but can also be diagnosed in older subjects, as shown in our SLR. Some other IMDs have not been reported in the present study. We have not identified any case of phenylketonuria (PKU), which is one of the most frequent IMDs. This result could be explained by the existence of a systematic newborn screening (NBS) for PKU in many countries. However, late diagnosis of PKU is still possible in (1) people born before NBS implementation, (2) people born in countries where NBS is not effective or does not exist at all. We can hypothesize that late diagnosis of PKU is made in patients before the age of 65 years or that these cases are not published.

The present study has some strengths and limitations. The main strength of this SLR relies on the fact that we used a rigorous methodology, following the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) 2020 checklist [7]. The main limitation of our study is the question of whether patients and diseases reported in the literature are representative or not of the real picture of IMDs in older patients, due to potential underreporting of metabolic geriatric cases and due to the risk for publication bias. There is also a diagnostic bias when we compare rare diseases with high costs treatments versus no treatment/low cost treatments—that is why we made the choice to split the included papers in two groups, the “SS” papers (usually funded by industry) versus “non SS, symptomatic” papers. It is clear from our results that the high prevalence of Fabry and GSD II in elderly was also driven by industry efforts. However, even when we excluded the SS studies from the analysis of symptoms, musculoskeletal symptoms were the most frequently reported, emphasizing their importance as a red flag for IMD suspicion in elderly. It is also worthy to point out that the use of the MeSH term “inborn error metabolism,” instead of the specific name of each IMD, can led to the non‐identification of papers which do not use the term “inborn error metabolism” as a MeSH term. This emphasizes the importance that the authors always select the most appropriate MeSH terms for your paper. Regarding the extraction of clinical data, we have to acknowledge a heterogeneous quality of papers, including some papers being published in so‐called “predatory journals” [273]. Moreover, clinical descriptions of case reports appeared to be also dependent of the specialty of the publishing team. Indeed, neurologists focus more on neurological aspects, dermatologists on skin lesions and so on. Thus, such heterogeneity to report patients might have influenced the analysis of clinical data that we have extracted from the selected papers.

In summary, the present SLR has identified a significant number of IMDs that can be diagnosed in older patients, from 65 years and over and sometimes in very old patients. This result indicates that clinical investigations for IMD in adults should not be limited to younger patients. Indeed, age should not be a barrier to limit diagnostic procedures for IMD as personalized therapy may help to ameliorate the quality of life of affected persons. Musculoskeletal symptoms, eventually associated with skin changes, appear to be a good field of investigations, but a wide range of symptoms could drive the clinicians to think about an IMD in older patients. A geriatric metabolic medicine could be developed in reference centers for IMD, in order to (1) develop diagnostic procedures in older people, (2) give the best care to patients with IMD as they get older. To date, specific education and training have been developed in the field of adult metabolic medicine [274]. We suggest that some knowledge dedicated to older patients should be added to the training competencies of physicians involved in adult metabolic medicine [275]. Finally, a geriatric metabolic medicine discipline could also be developed.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1. Supporting Information.